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1
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Chaudhary B, Arya P, Sharma V, Kumar P, Singla D, Grewal AS. Targeting anti-apoptotic mechanisms in tumour cells: Strategies for enhancing Cancer therapy. Bioorg Chem 2025; 159:108388. [PMID: 40107036 DOI: 10.1016/j.bioorg.2025.108388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 03/22/2025]
Abstract
Anti-cancer drug's cytotoxicity is determined by their ability to induce predetermined cell demise, commonly called apoptosis. The cancer-causing cells are able to evade cell death, which has been affiliated with both malignancy as well as resistance to cancer treatments. In order to avoid cell death, cancerous tumour cells often produce an abundance of anti-apoptotic proteins, becoming "dependent" on them. Consequently, protein inhibitors of cell death may prove to be beneficial as pharmacological targets for the future creation of cancer therapies. This article examines the molecular routes of apoptosis, its clinical manifestations, anti-cancer therapy options that target the intrinsic mechanism of apoptosis, proteins that prevent cell death, and members of the B-lymphoma-2 subset. In addition, novel approaches to cell death are highlighted, including how curcumin mitigates chemotherapy-induced apoptosis in healthy tissues and the various ways melatonin modifies apoptosis to improve cancer treatment efficacy, particularly through the TNF superfamily. Cancer treatment-induced increases in anti-apoptotic proteins lead to drug resistance; yet, ligands that trigger cell death by inhibiting these proteins are expected to improve chemotherapy's efficacy. The potential of frequency-modulated dietary phytochemicals as a cancer therapeutic pathway, including autophagy and apoptosis, is also explored. This approach may be more efficient than inhibition alone in overcoming drug resistance. Consequently, this method has the potential to allow for lower medication concentrations, reducing cytotoxicity and unwanted side effects.
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Affiliation(s)
- Benu Chaudhary
- Shri Ram College of Pharmacy, Ramba, Karnal, Haryana, India
| | - Preeti Arya
- Shri Ram College of Pharmacy, Ramba, Karnal, Haryana, India
| | - Vikas Sharma
- Guru Gobind Singh College of Pharmacy, Yamuna Nagar, Haryana, India
| | - Parveen Kumar
- NIMS Institute of Pharmacy, NIMS University, Jaipur, Rajasthan, India
| | - Deepak Singla
- Guru Gobind Singh College of Pharmacy, Yamuna Nagar, Haryana, India
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2
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Aba G, Abudukelimu S, de Winter M, Collu G, Bos E, Hamers SMWR, Hawinkels LJAC, van Montfoort N, Scheeren FA, Sharp TH. Inducing Cancer Cell Killing Using DNA Nanostructure-Mediated Superclustering of Death Receptors. NANO LETTERS 2025; 25:6310-6317. [PMID: 40197050 PMCID: PMC12007100 DOI: 10.1021/acs.nanolett.5c01122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 04/03/2025] [Accepted: 04/03/2025] [Indexed: 04/09/2025]
Abstract
Clustering of type-II tumor necrosis factor receptors (TNFRs) is required to induce intracellular signaling. Current methods for receptor clustering lack precise control over ligand valency and spatial organization, potentially limiting optimal TNFR activation, biological insight, and therapeutic efficacy. DNA nanostructures provide nanometer-precise control over molecular arrangement, allowing control of both ligand spacing and valency. Here, we produce a DNA nanostructure decorated with controlled numbers of engineered single-chain TNF-related apoptosis-inducing ligand (sc-TRAIL) trimers, which bind death receptor 5 (DR5) with native affinity and geometry and enable investigation of the geometric parameters influencing apoptotic pathway activation. We show that cell killing is affected by receptor valency and separation and enhanced by superclustering sc-TRAIL trimers, which can induce cell killing in human primary pancreatic and colorectal cancer organoids. Together, our data show that control of receptor superclustering enhances our understanding of receptor activation mechanisms and informs the development of more effective cancer therapies.
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Affiliation(s)
- Göktuğ Aba
- Department
of Cell and Chemical Biology, Leiden University
Medical Center, 2333 ZG Leiden, The Netherlands
| | - Subinuer Abudukelimu
- Department
of Gastroenterology and Hepatology, Leiden
University Medical Center, 2333 ZG Leiden, The Netherlands
| | - Margot de Winter
- Department
of Cell and Chemical Biology, Leiden University
Medical Center, 2333 ZG Leiden, The Netherlands
| | - Gabriella Collu
- Department
of Cell and Chemical Biology, Leiden University
Medical Center, 2333 ZG Leiden, The Netherlands
| | - Erik Bos
- Department
of Cell and Chemical Biology, Leiden University
Medical Center, 2333 ZG Leiden, The Netherlands
| | - Sebastiaan M. W. R. Hamers
- Department
of Cell and Chemical Biology, Leiden University
Medical Center, 2333 ZG Leiden, The Netherlands
| | - Lukas J. A. C. Hawinkels
- Department
of Gastroenterology and Hepatology, Leiden
University Medical Center, 2333 ZG Leiden, The Netherlands
| | - Nadine van Montfoort
- Department
of Gastroenterology and Hepatology, Leiden
University Medical Center, 2333 ZG Leiden, The Netherlands
| | - Ferenc A. Scheeren
- Department
of Dermatology, Leiden University Medical
Center, 2333 ZG Leiden, The Netherlands
| | - Thomas H. Sharp
- Department
of Cell and Chemical Biology, Leiden University
Medical Center, 2333 ZG Leiden, The Netherlands
- School
of
Biochemistry, University of Bristol, Bristol, BS8 1TD, United Kingdom
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3
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Qiao X, Guo S, Meng Z, Gan H, Wu Z, Sun Y, Liu S, Dou G, Gu R. Advances in the study of death receptor 5. Front Pharmacol 2025; 16:1549808. [PMID: 40144653 PMCID: PMC11936945 DOI: 10.3389/fphar.2025.1549808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Accepted: 02/24/2025] [Indexed: 03/28/2025] Open
Abstract
DR5, a receptor with the highest affinity for TRAIL under physiological conditions, selectively induces apoptosis in specific target cells such as tumor and aberrant immune cells, while minimally affecting normal cells. The TRAIL-DR5 signaling pathway is a crucial regulatory mechanism when the body responds to various exogenous interference factors, including viruses, chemicals, and radiation. This pathway plays a vital role in maintaining physiological homeostasis and in the pathological development of various diseases. Different modulations of DR5, such as upregulation, activation, and antagonism, hold significant potential for therapeutic applications in tumors, cardiovascular diseases, autoimmune diseases, viral infections, and radiation injuries. This article provides an overview of the current research progress on DR5, including the status and prospects of its clinical applications.
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Affiliation(s)
- Xuan Qiao
- Graduate Collaborative Training Base of Academy of Military Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Shuang Guo
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Zhiyun Meng
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Hui Gan
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Zhuona Wu
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Yunbo Sun
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Shuchen Liu
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Guifang Dou
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Ruolan Gu
- Beijing Institute of Radiation Medicine, Beijing, China
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4
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El Yousfi Y, Fernández-Farrán FJ, Oliver FJ, López-Rivas A, Yerbes R. Regulation of ER stress-induced apoptotic and inflammatory responses via YAP/TAZ-mediated control of the TRAIL-R2/DR5 signaling pathway. Cell Death Discov 2025; 11:42. [PMID: 39904986 PMCID: PMC11794427 DOI: 10.1038/s41420-025-02335-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/10/2025] [Accepted: 01/28/2025] [Indexed: 02/06/2025] Open
Abstract
In tumors, cancer cells are frequently exposed to adverse environmental conditions that result in endoplasmic reticulum (ER) stress. Mechanical signals emerging from extracellular matrix (ECM) rigidity and cell shape regulate the activity of transcriptional co-activators Yes-associated protein (YAP) and its paralog Transcriptional Coactivator with PDZ-binding motif (TAZ). However, the role of ECM rigidity and YAP/TAZ in tumor cell fate decisions under ER stress remains relatively unexplored. Our results suggest that the YAP/TAZ system plays an important role in the control of ER stress-induced cell death by mechanical signaling arising from ECM stiffness in tumor cells. Mechanistically, YAP/TAZ regulates apoptosis induced by ER stress in tumor cells by controlling the activation of the TRAIL-R2/DR5-mediated extrinsic apoptotic pathway through a dual mechanism. On the one hand, the YAP/TAZ system prevents intracellular TRAIL-R2/DR5 clustering in tumor cells. On the other hand, it inhibits cFLIP down-regulation in tumor cells experiencing ER stress. In addition, YAP/TAZ controls the expression of pro-inflammatory interleukin-8 (IL-8/CXCL8) in tumor cells undergoing ER stress by a TRAIL-R2/DR5/caspase-8-dependent mechanism. Although other mechanisms may also be involved in controlling cell death and inflammation in tumor cells facing environmental stress, our results support a model in which regulation of the subcellular localization and activity of the YAP/TAZ transcriptional co-activators could contribute to the microenvironmental control of cell fate decisions in tumor cells undergoing ER stress.
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Affiliation(s)
- Y El Yousfi
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain
| | - F J Fernández-Farrán
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain
| | - F J Oliver
- Instituto de Parasitología y Biomedicina López Neyra, CSIC, Centro de Investigación Biomédica en Red de Cáncer CIBERONC, Granada, Spain
| | - A López-Rivas
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain
| | - R Yerbes
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain.
- Medical Physiology and Biophysics Department, Universidad de Sevilla and Instituto de Biomedicina de Sevilla (IBiS) (Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla), Seville, Spain.
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5
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Ouyang XM, Lin JH, Lin Y, Zhao XL, Huo YN, Liang LY, Huang YD, Xie GJ, Mi P, Ye ZY, Guleng B. The SERPINB4 gene mutation identified in twin patients with Crohn's disease impaires the intestinal epithelial cell functions. Sci Rep 2025; 15:2638. [PMID: 39838210 PMCID: PMC11751486 DOI: 10.1038/s41598-025-87280-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 01/17/2025] [Indexed: 01/23/2025] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory autoimmune disease of unknown etiology. To identify new targets related to the initiation of CD, we screened a pair of twins with CD, which is a rare phenomenon in the Chinese population, for genetic susceptibility factors. Whole-exome sequencing (WES) of these patients revealed a mutation in their SERPINB4 gene. Therefore, we studied a wider clinical cohort of patients with CD or ulcerous colitis (UC), healthy individuals, and those with a family history of CD for this mutation by Sanger sequencing. The single-nucleotide difference in the SERPINB4 gene, which was unique to the twin patients with CD, led to the substitution of lysine by a glutamic acid residue. Functional analysis indicated that this mutation of SERPINB4 inhibited the proliferation, colony formation, wound healing, and migration of intestinal epithelial cells (IECs). Furthermore, mutation of SERPINB4 induced apoptosis and activated apoptosis-related proteins in IECs, and a caspase inhibitor significantly reduced these effects. Transcriptome sequencing revealed that the expression of genes encoding proinflammatory proteins (IL1B, IL6, IL17, IL24, CCL2, and CXCR2) and key proteins in the immune response (S100A9, MMP3, and MYC) was significantly upregulated during SERPINB4 mutant-induced apoptosis. Thus, the heterozygous SERPINB4 gene mutation causes the dysfunction of IECs, which would disrupt the intestinal epithelial barrier and contribute to the development of intestinal inflammation. The activation of SERPINB4 might represent a novel therapeutic target for inflammatory bowel disease.
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Affiliation(s)
- Xiao-Mei Ouyang
- Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China
| | - Jun-Hui Lin
- Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China
| | - Ying Lin
- Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China
| | - Xian-Ling Zhao
- Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China
| | - Ya-Ni Huo
- Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China
| | - Lai-Ying Liang
- Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China
| | - Yong-Dong Huang
- Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China
| | - Gui-Jing Xie
- Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China
| | - Peng Mi
- Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China
| | - Zhen-Yu Ye
- Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China
| | - Bayasi Guleng
- Department of Gastroenterology, The National Key Clinical Specialty, Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Key Laboratory for Intestinal Microbiome and Human Health of Xiamen, Zhongshan Hospital of Xiamen University, Xiamen, 361004, China.
- Cancer Research Center, Department of Digestive Disease and Institute of Microbial Ecology, School of Medicine, Xiamen University, Xiamen, 361004, China.
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6
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Mo C, Wei N, Li T, Ahmed Bhat M, Mohammadi M, Kuang C. CDK9 inhibitors for the treatment of solid tumors. Biochem Pharmacol 2024; 229:116470. [PMID: 39127153 DOI: 10.1016/j.bcp.2024.116470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 08/04/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
Cyclin-dependent kinase 9 (CDK9) regulates mRNA transcription by promoting RNA Pol II elongation. CDK9 is now emerging as a potential therapeutic target for cancer, since its overexpression has been found to correlate with cancer development and worse clinical outcomes. While much work on CDK9 inhibition has focused on hematologic malignancies, the role of this cancer driver in solid tumors is starting to come into focus. Many solid cancers also overexpress CDK9 and depend on its activity to promote downstream oncogenic signaling pathways. In this review, we summarize the latest knowledge of CDK9 biology in solid tumors and the studies of small molecule CDK9 inhibitors. We discuss the results of the latest clinical trials of CDK9 inhibitors in solid tumors, with a focus on key issues to consider for improving the therapeutic impact of this drug class.
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Affiliation(s)
- Christiana Mo
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA
| | - Ning Wei
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY, USA
| | - Terence Li
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY, USA
| | - Muzaffer Ahmed Bhat
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY, USA
| | - Mahshid Mohammadi
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY, USA
| | - Chaoyuan Kuang
- Department of Oncology, Montefiore Einstein, Bronx, NY, USA; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY, USA.
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7
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Yin Z, Li H, Zhao H, Bentum-Ennin L, Xia Y, Wang Z, Hu W, Gu H, Zhang S, Li G. CircRAPGEF5 acts as a modulator of RAS/RAF/MEK/ERK signaling during colorectal carcinogenesis. Heliyon 2024; 10:e36133. [PMID: 39229520 PMCID: PMC11369509 DOI: 10.1016/j.heliyon.2024.e36133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 09/05/2024] Open
Abstract
Mutations in oncogenes such as KRAS, NRAS and BRAF promote the growth and survival of tumors, while excessive RAS/RAF/MEK/ERK activation inhibits tumor growth. In this study we examined the precise regulatory machinery that maintains a moderate RAS/RAF/MEK/ERK pathway activation during CRC. Here, using bioinformatic analysis, transcriptomic profiling, gene silencing and cellular assays we discovered that a circular RNA, circRAPGEF5, is significantly upregulated in KRAS mutant colorectal cancer (CRC) cells. CircRAPGEF5 suppressed mutant and constitutively activated KRAS and the expression of the death receptor TNFRSF10A. Silencing of circRAPGEF5-induced RAS/RAF/MEK/ERK signaling hyperactivation and apoptosis in CRC cells suggesting that an upregulation of circRAPEF5 may suppress the expression of TNFRSF10A and aid CRC progression by preventing apoptosis, while the direct interactions between circRAPGEF5 and elements of the RAS/RAF/MEK/ERK pathway was not identified, which nevertheless can be the basis for future research. Moreover, EIF4A3, was observed to share a similar expression pattern with circRAPEF5 and demonstrated to be a major controller of circRAPGEF5 via the promotion of circRAPGEF5 circularization and its silencing reduced circRAPGEF5 levels. Taken together, our findings reveal a mechanism of accurate RAS/RAF/MEK/ERK signaling regulation during CRC progression maintained by upregulation of circRAPGEF5 which may be a plausible target for future clinical applications that seek to induce CRC cell apoptosis via the RAS/RAF/MEK/ERK signaling pathway.
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Affiliation(s)
- Zhipeng Yin
- Department of Gastrointestinal Surgery, The People's Hospital of Bozhou, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
| | - Hao Li
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Heng Zhao
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Lutterodt Bentum-Ennin
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Yang Xia
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Genome Center, KingMed Center for Clinical Laboratory Co., Ltd., Hefei, China
| | - Zaibiao Wang
- Department of Gastrointestinal Surgery, The People's Hospital of Bozhou, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
| | - Wanglai Hu
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Translational Research Institute, People's Hospital of Zhengzhou University, Academy of Medical Science, Henan International Joint Laboratory of Non-coding RNA and Metabolism in Cancer, Zhengzhou University, Zhengzhou, China
| | - Hao Gu
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Shangxin Zhang
- Department of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guangyun Li
- Department of Gastrointestinal Surgery, The People's Hospital of Bozhou, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
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8
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Ticona-Pérez FV, Chen X, Pandiella A, Díaz-Rodríguez E. Multiple mechanisms contribute to acquired TRAIL resistance in multiple myeloma. Cancer Cell Int 2024; 24:275. [PMID: 39098932 PMCID: PMC11299348 DOI: 10.1186/s12935-024-03466-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 07/29/2024] [Indexed: 08/06/2024] Open
Abstract
Multiple Myeloma (MM) prognosis has recently improved thanks to the incorporation of new therapies to the clinic. Nonetheless, it is still a non-curable malignancy. Targeting cancer cells with agents inducing cell death has been an appealing alternative investigated over the years, as is the case of TRAIL, an agonist of DR4 and DR5 death receptors. This pathway, involved in apoptosis triggering, has demonstrated efficacy on MM cells. In this research, we have investigated the sensitivity of a panel of MM cells to this agent and generated TRAIL-resistant models by continuous culture of sensitive cells with this peptide. Using genomic and biochemical approaches, the mechanisms underlying resistance were investigated. In TRAIL-resistant cells, a strong reduction in cell-surface receptor levels was detected and impaired the apoptotic machinery to respond to the treatment, enabling cells to efficiently form the Death Inducing Signalling Complex. In addition, an upregulation of the inhibitory protein c-FLIP was detected. Even though the manipulation of these proteins was able to modify cellular responses to TRAIL, it was not complete, pointing to other mechanisms involved in TRAIL resistance.
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Affiliation(s)
- Fany V Ticona-Pérez
- Instituto de Biología Molecular y Celular del Cáncer. CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain
| | - Xi Chen
- Instituto de Biología Molecular y Celular del Cáncer. CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain
| | - Atanasio Pandiella
- Instituto de Biología Molecular y Celular del Cáncer. CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
- CIBERONC, Madrid, Spain.
- IBSAL, Salamanca, Spain.
| | - Elena Díaz-Rodríguez
- Instituto de Biología Molecular y Celular del Cáncer. CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, Spain.
- CIBERONC, Madrid, Spain.
- IBSAL, Salamanca, Spain.
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9
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Masum AA, Aoki S, Rahman MM, Hisamatsu Y. Chemical synthetic approaches to mimic the TRAIL: promising cancer therapeutics. RSC Med Chem 2024; 15:d4md00183d. [PMID: 39246747 PMCID: PMC11376135 DOI: 10.1039/d4md00183d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 07/29/2024] [Indexed: 09/10/2024] Open
Abstract
Apoptosis is programmed cell death that eliminates undesired cells to maintain homeostasis in metazoan. Aberration of this process may lead to cancer genesis. The tumor necrosis factor related apoptosis inducing ligand (TRAIL) induces apoptosis in cancer cells after ligation with death receptors (DR4/DR5) while sparing most normal cells. Therefore, strategies to induce apoptosis in cancer cells by mimicking the TRAIL emerge as a promising therapeutic tool. Hence, approaches are taken to develop TRAIL/DR-based cancer therapeutics. The recombinant soluble TRAIL (rhTRAIL) and death receptor agonistic antibodies were produced and tested pre-clinically and clinically. Pre-clinical and clinical trial data demonstrate that these therapeutics are safe and relatively well tolerated. But some of these therapeutics failed to exert adequate efficacy in clinical settings. Besides these biotechnologically derived therapeutics, a few chemically synthesized therapeutics are reported. Some of these therapeutics exert considerable efficacy in vitro and in vivo. In this review, we will discuss chemically synthesized TRAIL/DR-based therapeutics, their chemical and biological behaviour, design concepts and strategies that may contribute to further improvement of TRAIL/DR-based therapeutics.
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Affiliation(s)
- Abdullah-Al Masum
- Department of Pharmaceutical Sciences, North South University Bashundhara R/A Dhaka-1229 Bangladesh
| | - Shin Aoki
- Faculty of Pharmaceutical Sciences, Tokyo University of Science 2641 Yamazaki, Noda-shi Chiba 278-8510 Japan
- Research Institute for Science and Technology, Tokyo University of Science 2641 Yamazaki, Noda-shi Chiba 278-8510 Japan
- Research Institute for Biomedical Sciences, Tokyo University of Science 2641 Yamazaki, Noda-shi Chiba 278-8510 Japan
| | - Md Mahbubur Rahman
- Department of Pharmaceutical Sciences, North South University Bashundhara R/A Dhaka-1229 Bangladesh
| | - Yosuke Hisamatsu
- Graduate School of Pharmaceutical Sciences, Nagoya City University Mizuho-Ku Nagoya 467-8603 Japan
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10
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Xu Q, Li J, Zhuo L, Gao H, Yang Y, Li W. RACGAP1 is a pivotal gene in lung adenocarcinoma-associated membranous nephropathy: Based on comprehensive bioinformatics analysis and machine learning. Int Immunopharmacol 2024; 139:112783. [PMID: 39068752 DOI: 10.1016/j.intimp.2024.112783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 06/05/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND This study performs a detailed bioinformatics and machine learning analysis to investigate the genetic foundations of membranous nephropathy (MN) in lung adenocarcinoma (LUAD). METHODS In this study, the gene expression profiles of MN microarray datasets (GSE99339) and LUAD dataset (GSE43767) were downloaded from the Gene Expression Omnibus database, common differentially expressed genes (DEGs) were obtained using the limma R package. The biological functions were analyzed with R Cluster Profiler package according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Machine learning algorithms, including LASSO regression, support vector machine (SVM), Random Forest, and Boruta analysis, were applied to identify hubgenes linked to LUAD-associated MN. These genes' prognostic values were evaluated in the TCGA-LUAD cohort and validated through immunohistochemistry on renal biopsy specimens. RESULTS A total of 36 DEGs in common were identified for downstream analyses. Functional enrichment analysis highlighted the involvement of the Toll-like receptor 4 pathway and several immune recognition pathways in LUAD-associated MN. COL3A1, PSENEN, RACGAP1, and TNFRSF10B were identified as hub genes in LUAD-associated MN using machine learning algorithms. ROC analysis demonstrated their effective discrimination of MN with high accuracy. Survival analysis showed that lung adenocarcinoma patients with higher expression of these genes had significantly reduced overall survival. In patients with lung adenocarcinoma-associated MN, RACGAP1, COL3A1, PSENEN, and TNFRSF10B were higher expressed in the glomerular, especially RACGAP1, indicating an important role in the pathogenesis of LUAD-associated membranous nephropathy. CONCLUSIONS Our study underscores the critical role of RACGAP1, COL3A1, PSENEN, and TNFRSF10B in the development of LUAD-associated MN, providing important insights for future research and the development of potential therapeutic strategies.
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Affiliation(s)
- Qianqian Xu
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Jiayi Li
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China; Department of Nephrology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Li Zhuo
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Hongmei Gao
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Yue Yang
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Wenge Li
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China; Department of Nephrology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
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11
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Han JH, Park SY, Myung SH, Park J, Chang JH, Kim TH. Suppression of neointimal hyperplasia induced by arteriovenous anastomosis and balloon injury in rats by multimeric tumor necrosis factor-related apoptosis-inducing ligand. Mol Cells 2024; 47:100075. [PMID: 38823606 PMCID: PMC11227017 DOI: 10.1016/j.mocell.2024.100075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 04/30/2024] [Accepted: 05/26/2024] [Indexed: 06/03/2024] Open
Abstract
Excessive blood vessel wall thickening, known as intimal hyperplasia, can result from injury or inflammation and increase the risk of vascular diseases. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays key roles in tumor surveillance, autoimmune diseases, and apoptosis; however, its role in vascular stenosis remains controversial. Treatment with recombinant isoleucine zipper hexamerization domain soluble TRAIL (ILz(6):TRAIL) significantly inhibited the progression of neointimal hyperplasia (NH) induced by anastomosis of the carotid artery and jugular vein dose dependently, and adenovirus expressing secretable ILz(6):TRAIL also inhibited NH induced by balloon injury in the femoral artery of rats. This study demonstrated the preventive and partial regressive effects of ILz(6):TRAIL on anastomosis of the carotid artery and jugular vein- or balloon-induced NH.
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Affiliation(s)
- Ji Hye Han
- Department of Biochemistry, Chosun University School of Medicine, Gwangju 61452, Republic of Korea
| | - Sun-Young Park
- Department of Biochemistry, Chosun University School of Medicine, Gwangju 61452, Republic of Korea
| | - Seung-Hyun Myung
- Department of Biochemistry, Chosun University School of Medicine, Gwangju 61452, Republic of Korea
| | - Junghee Park
- Department of Biochemistry, Chosun University School of Medicine, Gwangju 61452, Republic of Korea
| | - Jeong Hwan Chang
- Surgery Department, Chang Surgical Clinic, Gwangju 62274, Republic of Korea
| | - Tae-Hyoung Kim
- Department of Biochemistry, Chosun University School of Medicine, Gwangju 61452, Republic of Korea.
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12
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Kim S, Lee KW, Yoo Y, Park SH, Lee JW, Jeon S, Illia S, Joshi P, Park HW, Lo HE, Seo J, Kim Y, Chang M, Lee TJ, Seo JB, Kim SH, Croce CM, Kim I, Suh SS, Jeon YJ. MiR-29 and MiR-140 regulate TRAIL-induced drug tolerance in lung cancer. Anim Cells Syst (Seoul) 2024; 28:184-197. [PMID: 38693921 PMCID: PMC11062278 DOI: 10.1080/19768354.2024.2345644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 04/11/2024] [Indexed: 05/03/2024] Open
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has chemotherapeutic potential as a regulator of an extrinsic apoptotic ligand, but its effect as a drug is limited by innate and acquired resistance. Recent findings suggest that an intermediate drug tolerance could mediate acquired resistance, which has made the main obstacle for limited utility of TRAIL as an anti-cancer therapeutics. We propose miRNA-dependent epigenetic modification drives the drug tolerant state in TRAIL-induced drug tolerant (TDT). Transcriptomic analysis revealed miR-29 target gene activation in TDT cells, showing oncogenic signature in lung cancer. Also, the restored TRAIL-sensitivity was associated with miR-29ac and 140-5p expressions, which is known as tumor suppressor by suppressing oncogenic protein RSK2 (p90 ribosomal S6 kinase), further confirmed in patient samples. Moreover, we extended this finding into 119 lung cancer cell lines from public data set, suggesting a significant correlation between TRAIL-sensitivity and RSK2 mRNA expression. Finally, we found that increased RSK2 mRNA is responsible for NF-κB activation, which we previously showed as a key determinant in both innate and acquired TRAIL-resistance. Our findings support further investigation of miR-29ac and -140-5p inhibition to maintain TRAIL-sensitivity and improve the durability of response to TRAIL in lung cancer.
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Affiliation(s)
- Suyeon Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Ki Wook Lee
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Yongjin Yoo
- Department of Stem Cell Biology and Regenerative Medicine Institute, Stanford University, Stanford, CA, USA
| | - Sang Hee Park
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Ji Won Lee
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Suhyun Jeon
- Department of Biosciences, Mokpo National University, Muan, Republic of Korea
| | - Shaginyan Illia
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Pooja Joshi
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Hyun Woo Park
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Han-En Lo
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Jimin Seo
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Yeonwoo Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Min Chang
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - Tae Jin Lee
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jong Bae Seo
- Department of Biosciences, Mokpo National University, Muan, Republic of Korea
| | - Sung-Hak Kim
- Department of Animal Science, Chonnam National University, Gwangju, Republic of Korea
| | - Carlo M. Croce
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Inki Kim
- ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea
| | - Sung-Suk Suh
- Department of Biosciences, Mokpo National University, Muan, Republic of Korea
| | - Young-Jun Jeon
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
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13
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Kuranaga Y, Yu B, Osuka S, Zhang H, Devi NS, Bae S, Van Meir EG. Targeting Integrin α3 Blocks β1 Maturation, Triggers Endoplasmic Reticulum Stress, and Sensitizes Glioblastoma Cells to TRAIL-Mediated Apoptosis. Cells 2024; 13:753. [PMID: 38727288 PMCID: PMC11083687 DOI: 10.3390/cells13090753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/16/2024] [Accepted: 04/18/2024] [Indexed: 05/13/2024] Open
Abstract
Glioblastoma (GBM) is a devastating brain cancer for which new effective therapies are urgently needed. GBM, after an initial response to current treatment regimens, develops therapeutic resistance, leading to rapid patient demise. Cancer cells exhibit an inherent elevation of endoplasmic reticulum (ER) stress due to uncontrolled growth and an unfavorable microenvironment, including hypoxia and nutrient deprivation. Cancer cells utilize the unfolded protein response (UPR) to maintain ER homeostasis, and failure of this response promotes cell death. In this study, as integrins are upregulated in cancer, we have evaluated the therapeutic potential of individually targeting all αβ1 integrin subunits using RNA interference. We found that GBM cells are uniquely susceptible to silencing of integrin α3. Knockdown of α3-induced proapoptotic markers such as PARP cleavage and caspase 3 and 8 activation. Remarkably, we discovered a non-canonical function for α3 in mediating the maturation of integrin β1. In its absence, generation of full length β1 was reduced, immature β1 accumulated, and the cells underwent elevated ER stress with upregulation of death receptor 5 (DR5) expression. Targeting α3 sensitized TRAIL-resistant GBM cancer cells to TRAIL-mediated apoptosis and led to growth inhibition. Our findings offer key new insights into integrin α3's role in GBM survival via the regulation of ER homeostasis and its value as a therapeutic target.
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Affiliation(s)
- Yuki Kuranaga
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Y.K.); (S.O.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Bing Yu
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA; (B.Y.); (H.Z.); (N.S.D.)
| | - Satoru Osuka
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Y.K.); (S.O.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Hanwen Zhang
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA; (B.Y.); (H.Z.); (N.S.D.)
| | - Narra S. Devi
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA; (B.Y.); (H.Z.); (N.S.D.)
| | - Sejong Bae
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
- Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Erwin G. Van Meir
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Y.K.); (S.O.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA; (B.Y.); (H.Z.); (N.S.D.)
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14
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Guerrache A, Micheau O. TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling. Cells 2024; 13:521. [PMID: 38534365 PMCID: PMC10968836 DOI: 10.3390/cells13060521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/01/2024] [Accepted: 03/14/2024] [Indexed: 03/28/2024] Open
Abstract
TNF-related apoptosis-inducing ligand (TRAIL or Apo2 or TNFSF10) belongs to the TNF superfamily. When bound to its agonistic receptors, TRAIL can induce apoptosis in tumour cells, while sparing healthy cells. Over the last three decades, this tumour selectivity has prompted many studies aiming at evaluating the anti-tumoral potential of TRAIL or its derivatives. Although most of these attempts have failed, so far, novel formulations are still being evaluated. However, emerging evidence indicates that TRAIL can also trigger a non-canonical signal transduction pathway that is likely to be detrimental for its use in oncology. Likewise, an increasing number of studies suggest that in some circumstances TRAIL can induce, via Death receptor 5 (DR5), tumour cell motility, potentially leading to and contributing to tumour metastasis. While the pro-apoptotic signal transduction machinery of TRAIL is well known from a mechanistic point of view, that of the non-canonical pathway is less understood. In this study, we the current state of knowledge of TRAIL non-canonical signalling.
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Affiliation(s)
- Abderrahmane Guerrache
- Université de Bourgogne, 21000 Dijon, France
- INSERM Research Center U1231, «Equipe DesCarTes», 21000 Dijon, France
| | - Olivier Micheau
- Université de Bourgogne, 21000 Dijon, France
- INSERM Research Center U1231, «Equipe DesCarTes», 21000 Dijon, France
- Laboratoire d’Excellence LipSTIC, 21000 Dijon, France
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15
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Luo Y, Hao H, Wang Z, Ong CY, Dutcher R, Xu Y, Liu J, Pedersen LC, Xu D. Heparan sulfate promotes TRAIL-induced tumor cell apoptosis. eLife 2024; 12:RP90192. [PMID: 38265424 PMCID: PMC10945736 DOI: 10.7554/elife.90192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2024] Open
Abstract
TRAIL (TNF-related apoptosis-inducing ligand) is a potent inducer of tumor cell apoptosis through TRAIL receptors. While it has been previously pursued as a potential anti-tumor therapy, the enthusiasm subsided due to unsuccessful clinical trials and the fact that many tumors are resistant to TRAIL. In this report, we identified heparan sulfate (HS) as an important regulator of TRAIL-induced apoptosis. TRAIL binds HS with high affinity (KD = 73 nM) and HS induces TRAIL to form higher-order oligomers. The HS-binding site of TRAIL is located at the N-terminus of soluble TRAIL, which includes three basic residues. Binding to cell surface HS plays an essential role in promoting the apoptotic activity of TRAIL in both breast cancer and myeloma cells, and this promoting effect can be blocked by heparin, which is commonly administered to cancer patients. We also quantified HS content in several lines of myeloma cells and found that the cell line showing the most resistance to TRAIL has the least expression of HS, which suggests that HS expression in tumor cells could play a role in regulating sensitivity towards TRAIL. We also discovered that death receptor 5 (DR5), TRAIL, and HS can form a ternary complex and that cell surface HS plays an active role in promoting TRAIL-induced cellular internalization of DR5. Combined, our study suggests that TRAIL-HS interactions could play multiple roles in regulating the apoptotic potency of TRAIL and might be an important point of consideration when designing future TRAIL-based anti-tumor therapy.
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Affiliation(s)
- Yin Luo
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New YorkBuffaloUnited States
| | - Huanmeng Hao
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New YorkBuffaloUnited States
| | - Zhangjie Wang
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North CarolinaChapel HillUnited States
| | - Chih Yean Ong
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New YorkBuffaloUnited States
| | - Robert Dutcher
- Macromolecular Structure Group, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of HealthResearch Triangle ParkUnited States
| | - Yongmei Xu
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North CarolinaChapel HillUnited States
| | - Jian Liu
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North CarolinaChapel HillUnited States
| | - Lars C Pedersen
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of HealthResearch Triangle ParkUnited States
| | - Ding Xu
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New YorkBuffaloUnited States
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16
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Steitz AM, Schröder C, Knuth I, Keber CU, Sommerfeld L, Finkernagel F, Jansen JM, Wagner U, Müller-Brüsselbach S, Worzfeld T, Huber M, Beutgen VM, Graumann J, Pogge von Strandmann E, Müller R, Reinartz S. TRAIL-dependent apoptosis of peritoneal mesothelial cells by NK cells promotes ovarian cancer invasion. iScience 2023; 26:108401. [PMID: 38047087 PMCID: PMC10692662 DOI: 10.1016/j.isci.2023.108401] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/04/2023] [Accepted: 11/03/2023] [Indexed: 12/05/2023] Open
Abstract
A crucial requirement for metastasis formation in ovarian high-grade serous carcinoma (HGSC) is the disruption of the protective peritoneal mesothelium. Using co-culture systems of primary human cells, we discovered that tumor-associated NK cells induce TRAIL-dependent apoptosis in mesothelial cells via death receptors DR4 and DR5 upon encounter with activated T cells. Upregulation of TRAIL expression in NK cells concomitant with enhanced cytotoxicity toward mesothelial cells was driven predominantly by T-cell-derived TNFα, as shown by affinity proteomics-based analysis of the T cell secretome in conjunction with functional studies. Consistent with these findings, we detected apoptotic mesothelial cells in the peritoneal fluid of HGSC patients. In contrast to mesothelial cells, HGSC cells express negligible levels of both DR4 and DR5 and are TRAIL resistant, indicating cell-type-selective killing by NK cells. Our data point to a cooperative action of T and NK in breaching the mesothelial barrier in HGSC patients.
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Affiliation(s)
- Anna Mary Steitz
- Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Clarissa Schröder
- Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Isabel Knuth
- Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Corinna U. Keber
- Institute for Pathology, Philipps University, 35043 Marburg, Germany
| | - Leah Sommerfeld
- Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Florian Finkernagel
- Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Julia M. Jansen
- Clinic for Gynecology, Gynecological Oncology, Gynecological Endocrinology, University Hospital (UKGM), 35043 Marburg, Germany
| | - Uwe Wagner
- Clinic for Gynecology, Gynecological Oncology, Gynecological Endocrinology, University Hospital (UKGM), 35043 Marburg, Germany
| | - Sabine Müller-Brüsselbach
- Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Thomas Worzfeld
- Institute of Pharmacology, Biochemical-Pharmacological Center (BPC), Philipps University, 35043 Marburg, Germany
| | - Magdalena Huber
- Institute of Systems Immunology, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Vanessa M. Beutgen
- Institute of Translational Proteomics, Philipps University, 35043 Marburg, Germany
- Core Facility Translational Proteomics, Philipps University, 35043 Marburg, Germany
| | - Johannes Graumann
- Institute of Translational Proteomics, Philipps University, 35043 Marburg, Germany
- Core Facility Translational Proteomics, Philipps University, 35043 Marburg, Germany
| | - Elke Pogge von Strandmann
- Institute for Tumor Immunology, Center for Tumor Biology and Immunology (ZTI), Clinic for Hematology, Oncology and Immunology, Philipps University, 35043 Marburg, Germany
| | - Rolf Müller
- Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
| | - Silke Reinartz
- Translational Oncology Group, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany
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17
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Vlachava VM, Seirafian S, Fielding CA, Kollnberger S, Aicheler RJ, Hughes J, Baker A, Weekes MP, Forbes S, Wilkinson GWG, Wang ECY, Stanton RJ. HCMV-secreted glycoprotein gpUL4 inhibits TRAIL-mediated apoptosis and NK cell activation. Proc Natl Acad Sci U S A 2023; 120:e2309077120. [PMID: 38011551 PMCID: PMC10710050 DOI: 10.1073/pnas.2309077120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 10/07/2023] [Indexed: 11/29/2023] Open
Abstract
Human cytomegalovirus (HCMV) is a paradigm of pathogen immune evasion and sustains lifelong persistent infection in the face of exceptionally powerful host immune responses through the concerted action of multiple immune-evasins. These reduce NK cell activation by inhibiting ligands for activating receptors, expressing ligands for inhibitory receptors, or inhibiting synapse formation. However, these functions only inhibit direct interactions with the infected cell. To determine whether the virus also expresses soluble factors that could modulate NK function at a distance, we systematically screened all 170 HCMV canonical protein-coding genes. This revealed that UL4 encodes a secreted and heavily glycosylated protein (gpUL4) that is expressed with late-phase kinetics and is capable of inhibiting NK cell degranulation. Analyses of gpUL4 binding partners by mass spectrometry identified an interaction with TRAIL. gpUL4 bound TRAIL with picomolar affinity and prevented TRAIL from binding its receptor, thus acting as a TRAIL decoy receptor. TRAIL is found in both soluble and membrane-bound forms, with expression of the membrane-bound form strongly up-regulated on NK cells in response to interferon. gpUL4 inhibited apoptosis induced by soluble TRAIL, while also binding to the NK cell surface in a TRAIL-dependent manner, where it blocked NK cell degranulation and cytokine secretion. gpUL4 therefore acts as an immune-evasin by inhibiting both soluble and membrane-bound TRAIL and is a viral-encoded TRAIL decoy receptor. Interestingly, gpUL4 could also suppress NK responses to heterologous viruses, suggesting that it may act as a systemic virally encoded immunosuppressive agent.
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Affiliation(s)
- Virginia-Maria Vlachava
- Infection and Immunity, School of Medicine, Cardiff University, CardiffCF14 4XN, United Kingdom
| | - Sepehr Seirafian
- Infection and Immunity, School of Medicine, Cardiff University, CardiffCF14 4XN, United Kingdom
| | - Ceri A. Fielding
- Infection and Immunity, School of Medicine, Cardiff University, CardiffCF14 4XN, United Kingdom
| | - Simon Kollnberger
- Infection and Immunity, School of Medicine, Cardiff University, CardiffCF14 4XN, United Kingdom
| | - Rebecca J. Aicheler
- Department of Biomedical Sciences, Cardiff School of Sport and Health Sciences, Cardiff Metropolitan University, CardiffCF5 2YB, United Kingdom
| | - Joseph Hughes
- Centre for Virus Research, School of Infection & Immunity, Glasgow University, GlasgowG61 1QH, United Kingdom
| | - Alexander Baker
- Infection and Immunity, School of Medicine, Cardiff University, CardiffCF14 4XN, United Kingdom
| | - Michael P. Weekes
- Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, CambridgeCB2 0XY, United Kingdom
| | - Simone Forbes
- Infection and Immunity, School of Medicine, Cardiff University, CardiffCF14 4XN, United Kingdom
| | - Gavin W. G. Wilkinson
- Infection and Immunity, School of Medicine, Cardiff University, CardiffCF14 4XN, United Kingdom
| | - Eddie C. Y. Wang
- Infection and Immunity, School of Medicine, Cardiff University, CardiffCF14 4XN, United Kingdom
| | - Richard J. Stanton
- Infection and Immunity, School of Medicine, Cardiff University, CardiffCF14 4XN, United Kingdom
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18
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Wang L, Deng R, Chen S, Tian R, Guo M, Chen Z, Zhang Y, Li H, Liu Q, Tang S, Zhu H. Carboxypeptidase A4 negatively regulates HGS-ETR1/2-induced pyroptosis by forming a positive feedback loop with the AKT signalling pathway. Cell Death Dis 2023; 14:793. [PMID: 38049405 PMCID: PMC10696061 DOI: 10.1038/s41419-023-06327-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 11/12/2023] [Accepted: 11/22/2023] [Indexed: 12/06/2023]
Abstract
Pyroptosis, a mode of inflammatory cell death, has recently gained significant attention. However, the underlying mechanism remains poorly understood. HGS-ETR1/2 is a humanized monoclonal antibody that can bind to DR4/5 on the cell membrane and induce cell apoptosis by activating the death receptor signalling pathway. In this study, by using morphological observation, fluorescence double staining, LDH release and immunoblot detection, we confirmed for the first time that HGS-ETR1/2 can induce GSDME-mediated pyroptosis in hepatocellular carcinoma cells. Our study found that both inhibition of the AKT signalling pathway and silencing of CPA4 promote pyroptosis, while the overexpression of CPA4 inhibits it. Furthermore, we identified a positive regulatory feedback loop is formed between CPA4 and AKT phosphorylation. Specifically, CPA4 modulates AKT phosphorylation by regulating the expression of the AKT phosphatase PP2A, while inhibition of the AKT signalling pathway leads to a decreased transcription and translation levels of CPA4. Our study reveals a novel mechanism of pyroptosis induced by HGS-ETR1/2, which may provide a crucial foundation for future investigations into cancer immunotherapy.
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Affiliation(s)
- Luoling Wang
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China
| | - Rilin Deng
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China
| | - Shuishun Chen
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China
| | - Renyun Tian
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China
| | - Mengmeng Guo
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China
| | - Zihao Chen
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China
| | - Yingdan Zhang
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China
| | - Huiyi Li
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China
| | - Qian Liu
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China
| | - Songqing Tang
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China.
| | - Haizhen Zhu
- Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China.
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Department of Pathogen Biology, Institute of Pathogen Biology and Immunology, School of Basic Medicine and Life Science, The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou, 571199, China.
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19
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Bai J, Wang H, Li C, Liu L, Wang J, Sun C, Zhang Q. A novel mitochondria-targeting compound exerts therapeutic effects against melanoma by inducing mitochondria-mediated apoptosis and autophagy in vitro and in vivo. ENVIRONMENTAL TOXICOLOGY 2023; 38:2608-2620. [PMID: 37466182 DOI: 10.1002/tox.23896] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 06/17/2023] [Accepted: 07/01/2023] [Indexed: 07/20/2023]
Abstract
Melanoma is the most invasive skin cancer, with a high mortality rate. However, existing therapeutic drugs have side effects, low reactivity, and lead to drug resistance. As the power source in cells, mitochondria play an important role in the survival of cancer cells and are an important target for tumor therapy. This study aimed to develop a new anti-melanoma compound that targets mitochondria, evaluate its effect on the proliferation and metastasis of melanoma cells, and explore its mechanism of action. The novel mitochondria-targeting compound, SCZ0148, was synthesized by modifying the structure of cyanine. Then, A375 and B16 cells were incubated with different concentrations of SCZ0148, and different doses of SCZ0148 were administered to A375 and B16 xenograft zebrafish. The results showed that SCZ0148 targeted mitochondria, had dose- and time-dependent effects on the proliferation of melanoma cell lines, and had no obvious side effects on normal cells. In addition, SCZ0148 induced melanoma cell apoptosis through the reactive oxygen species-mediated mitochondrial pathway of apoptosis and promoted autophagy. SCZ0148 significantly inhibited the migration of melanoma cells via a matrix metalloprotein 9-mediated pathway. Similarly, SCZ0148 inhibited melanoma cell proliferation in a concentration-dependent manner in vivo. In summary, SCZ0148 may be a novel anti-melanoma compound that targets mitochondria.
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Affiliation(s)
- Jun Bai
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, China
| | - Hailan Wang
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, China
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute of Public Health, Gusu School, Nanjing Medical University, Nanjing, China
| | - Chenwen Li
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, China
| | - Li Liu
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jianv Wang
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Changzhen Sun
- Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Qingbi Zhang
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, China
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20
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Luo Y, Hao H, Wang Z, Ong C, Dutcher R, Xu Y, Liu J, Pedersen LC, Xu D. Heparan sulfate promotes TRAIL-induced tumor cell apoptosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.26.550758. [PMID: 37546770 PMCID: PMC10402122 DOI: 10.1101/2023.07.26.550758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
TRAIL (TNF-related apoptosis-inducing ligand) is a potent inducer of tumor cell apoptosis through TRAIL receptors. While it has been previously pursued as a potential anti-tumor therapy, the enthusiasm subsided due to unsuccessful clinical trials and the fact that many tumors are resistant to TRAIL. In this report we identified heparan sulfate (HS) as an important regulator of TRAIL-induced apoptosis. TRAIL binds HS with high affinity (KD = 73 nM) and HS induces TRAIL to form higher-order oligomers. The HS-binding site of TRAIL is located at the N-terminus of soluble TRAIL, which includes three basic residues. Binding to cell surface HS plays an essential role in promoting the apoptotic activity of TRAIL in both breast cancer and myeloma cells, and this promoting effect can be blocked by heparin, which is commonly administered to cancer patients. We also quantified HS content in several lines of myeloma cells and found that the cell line showing the most resistance to TRAIL has the least expression of HS, which suggests that HS expression in tumor cells could play a role in regulating sensitivity towards TRAIL. We also discovered that death receptor 5 (DR5), TRAIL and HS can form a ternary complex and that cell surface HS plays an active role in promoting TRAIL-induced cellular internalization of DR5. Combined, our study suggests that TRAIL-HS interactions could play multiple roles in regulating the apoptotic potency of TRAIL and might be an important point of consideration when designing future TRAIL-based anti-tumor therapy.
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Affiliation(s)
- Yin Luo
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, Buffalo, NY 14214, USA
| | - Huanmeng Hao
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, Buffalo, NY 14214, USA
| | - Zhangjie Wang
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Chihyean Ong
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, Buffalo, NY 14214, USA
| | - Robert Dutcher
- Macromolecular Structure Group, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Yongmei Xu
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Jian Liu
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Lars C. Pedersen
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Ding Xu
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, Buffalo, NY 14214, USA
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21
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Haymour L, Jean M, Smulski C, Legembre P. CD95 (Fas) and CD95L (FasL)-mediated non-canonical signaling pathways. Biochim Biophys Acta Rev Cancer 2023; 1878:189004. [PMID: 37865305 DOI: 10.1016/j.bbcan.2023.189004] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/16/2023] [Indexed: 10/23/2023]
Abstract
Although the interaction of CD95L (also known as FasL) with its so-called death receptor CD95 (Fas) induces an apoptotic signal responsible for the elimination of infected and cancer cells and maintenance of tissue homeostasis, this receptor can also implement non apoptotic signaling pathways. This latter signaling is involved in metastatic dissemination in certain cancers and the severity of auto-immune disorders. The signaling complexity of this pair is increased by the fact that CD95 expression itself seems to contribute to oncogenesis via a CD95L-independent manner and, that both ligand and receptor might interact with other partners modulating their pathophysiological functions. Finally, CD95L itself can trigger cell signaling in immune cells rendering complex the interpretation of mouse models in which CD95 or CD95L are knocked out. Herein, we discuss these non-canonical responses and their biological functions.
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Affiliation(s)
- Layla Haymour
- UMR CNRS 7276, INSERM U1262, CRIBL, Université Limoges, Limoges, France
| | - Mickael Jean
- Université de Rennes, Institut des Sciences Chimiques de Rennes - UMR CNRS 6226 Equipe COrInt, Rennes F-35000, France
| | - Cristian Smulski
- Medical Physics Department, Centro Atómico Bariloche, Comisión Nacional de Energía Atómica (CNEA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Río Negro, Argentina
| | - Patrick Legembre
- UMR CNRS 7276, INSERM U1262, CRIBL, Université Limoges, Limoges, France.
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22
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El Yousfi Y, Mora-Molina R, López-Rivas A, Yerbes R. Role of the YAP/TAZ-TEAD Transcriptional Complex in the Metabolic Control of TRAIL Sensitivity by the Mevalonate Pathway in Cancer Cells. Cells 2023; 12:2370. [PMID: 37830584 PMCID: PMC10571597 DOI: 10.3390/cells12192370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/19/2023] [Accepted: 09/25/2023] [Indexed: 10/14/2023] Open
Abstract
Different studies have reported that inhibiting the mevalonate pathway with statins may increase the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), although the signaling mechanism leading to this sensitization remains largely unknown. We investigated the role of the YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)-TEAD (TEA/ATTS domain) transcriptional complex in the metabolic control of TRAIL sensitivity by the mevalonate pathway. We show that depleting nuclear YAP/TAZ in tumor cells, either via treatment with statins or by silencing YAP/TAZ expression with siRNAs, facilitates the activation of apoptosis by TRAIL. Furthermore, the blockage of TEAD transcriptional activity either pharmacologically or through the ectopic expression of a disruptor of the YAP/TAZ interaction with TEAD transcription factors, overcomes the resistance of tumor cells to the induction of apoptosis by TRAIL. Our results show that the mevalonate pathway controls cellular the FLICE-inhibitory protein (cFLIP) expression in tumor cells. Importantly, inhibiting the YAP/TAZ-TEAD signaling pathway induces cFLIP down-regulation, leading to a marked sensitization of tumor cells to apoptosis induction by TRAIL. Our data suggest that a combined strategy of targeting TEAD activity and selectively activating apoptosis signaling by agonists of apoptotic TRAIL receptors could be explored as a potential therapeutic approach in cancer treatment.
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Affiliation(s)
- Younes El Yousfi
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, 41092 Seville, Spain; (Y.E.Y.); (R.M.-M.); (A.L.-R.)
| | - Rocío Mora-Molina
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, 41092 Seville, Spain; (Y.E.Y.); (R.M.-M.); (A.L.-R.)
| | - Abelardo López-Rivas
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, 41092 Seville, Spain; (Y.E.Y.); (R.M.-M.); (A.L.-R.)
| | - Rosario Yerbes
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, 41092 Seville, Spain; (Y.E.Y.); (R.M.-M.); (A.L.-R.)
- Medical Physiology and Biophysics Department, Universidad de Sevilla and Instituto de Biomedicina de Sevilla (IBiS) (Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla), 41013 Seville, Spain
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23
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Gunalp S, Helvaci DG, Oner A, Bursalı A, Conforte A, Güner H, Karakülah G, Szegezdi E, Sag D. TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content. Front Immunol 2023; 14:1209249. [PMID: 37809073 PMCID: PMC10551148 DOI: 10.3389/fimmu.2023.1209249] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 08/30/2023] [Indexed: 10/10/2023] Open
Abstract
Background TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. TRAIL is investigated as a therapeutic agent in clinical trials due to its selective toxicity to transformed cells. Macrophages can be polarized into pro-inflammatory/tumor-fighting M1 macrophages or anti-inflammatory/tumor-supportive M2 macrophages and an imbalance between M1 and M2 macrophages can promote diseases. Therefore, identifying modulators that regulate macrophage polarization is important to design effective macrophage-targeted immunotherapies. The impact of TRAIL on macrophage polarization is not known. Methods Primary human monocyte-derived macrophages were pre-treated with either TRAIL or with DR4 or DR5-specific ligands and then polarized into M1, M2a, or M2c phenotypes in vitro. The expression of M1 and M2 markers in macrophage subtypes was analyzed by RNA sequencing, qPCR, ELISA, and flow cytometry. Furthermore, the cytotoxicity of the macrophages against U937 AML tumor targets was assessed by flow cytometry. TCGA datasets were also analyzed to correlate TRAIL with M1/M2 markers, and the overall survival of cancer patients. Results TRAIL increased the expression of M1 markers at both mRNA and protein levels while decreasing the expression of M2 markers at the mRNA level in human macrophages. TRAIL also shifted M2 macrophages towards an M1 phenotype. Our data showed that both DR4 and DR5 death receptors play a role in macrophage polarization. Furthermore, TRAIL enhanced the cytotoxicity of macrophages against the AML cancer cells in vitro. Finally, TRAIL expression was positively correlated with increased expression of M1 markers in the tumors from ovarian and sarcoma cancer patients and longer overall survival in cases with high, but not low, tumor macrophage content. Conclusions TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype via both DR4 and DR5. Our study defines TRAIL as a new regulator of macrophage polarization and suggests that targeting DRs can enhance the anti-tumorigenic response of macrophages in the tumor microenvironment by increasing M1 polarization.
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Affiliation(s)
- Sinem Gunalp
- Izmir Biomedicine and Genome Center, Izmir, Türkiye
- Department of Genomic Sciences and Molecular Biotechnology, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Türkiye
| | - Derya Goksu Helvaci
- Izmir Biomedicine and Genome Center, Izmir, Türkiye
- Faculty of Medicine, Dokuz Eylul University, Izmir, Türkiye
| | - Aysenur Oner
- Izmir Biomedicine and Genome Center, Izmir, Türkiye
- Department of Genomic Sciences and Molecular Biotechnology, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Türkiye
| | | | - Alessandra Conforte
- School of Biological and Chemical Sciences, University of Galway, Galway, Ireland
| | - Hüseyin Güner
- Izmir Biomedicine and Genome Center, Izmir, Türkiye
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Science, Abdullah Gül University, Kayseri, Türkiye
| | - Gökhan Karakülah
- Izmir Biomedicine and Genome Center, Izmir, Türkiye
- Department of Genomic Sciences and Molecular Biotechnology, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Türkiye
| | - Eva Szegezdi
- School of Biological and Chemical Sciences, University of Galway, Galway, Ireland
| | - Duygu Sag
- Izmir Biomedicine and Genome Center, Izmir, Türkiye
- Department of Genomic Sciences and Molecular Biotechnology, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Türkiye
- Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Türkiye
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24
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Ma N, Cheng K, Feng Q, Liu G, Liang J, Ma X, Chen Z, Lu Y, Wang X, He W, Xu H, Wu S, Zou J, Shi Q, Nie G, Zhao X. Nanoscale Organization of TRAIL Trimers using DNA Origami to Promote Clustering of Death Receptor and Cancer Cell Apoptosis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2206160. [PMID: 36890776 DOI: 10.1002/smll.202206160] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 01/19/2023] [Indexed: 06/08/2023]
Abstract
Through inducing death receptor (DR) clustering to activate downstream signaling, tumor necrosis factor related apoptosis inducing ligand (TRAIL) trimers trigger apoptosis of tumor cells. However, the poor agonistic activity of current TRAIL-based therapeutics limits their antitumor efficiency. The nanoscale spatial organization of TRAIL trimers at different interligand distances is still challenging, which is essential for the understanding of interaction pattern between TRAIL and DR. In this study, a flat rectangular DNA origami is employed as display scaffold, and an "engraving-printing" strategy is developed to rapidly decorate three TRAIL monomers onto its surface to form DNA-TRAIL3 trimer (DNA origami with surface decoration of three TRAIL monomers). With the spatial addressability of DNA origami, the interligand distances are precisely controlled from 15 to 60 nm. Through comparing the receptor affinity, agonistic activity and cytotoxicity of these DNA-TRAIL3 trimers, it is found that ≈40 nm is the critical interligand distance of DNA-TRAIL3 trimers to induce death receptor clustering and the resulting apoptosis.Finally, a hypothetical "active unit" model is proposed for the DR5 clustering induced by DNA-TRAIL3 trimers.
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Affiliation(s)
- Nana Ma
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Keman Cheng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Qingqing Feng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Guangna Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Jie Liang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Xiaotu Ma
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Zhiqiang Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Yichao Lu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Xinwei Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
| | - Wei He
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, Hubei, 430062, China
| | - Hu Xu
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, Hubei, 430062, China
| | - Shan Wu
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, Hubei, 430062, China
| | - Jiajia Zou
- Beijing Intell Nanomedicine, No. 9, Chengwan Street, Haidian District, Beijing, 100000, China
| | - Quanwei Shi
- Beijing Intell Nanomedicine, No. 9, Chengwan Street, Haidian District, Beijing, 100000, China
| | - Guangjun Nie
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiao Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
- IGDB-NCNST Joint Research Center, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
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25
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Karimi K, Mojtabavi S, Tehrany PM, Nejad MM, Rezaee A, Mohtashamian S, Hamedi E, Yousefi F, Salmani F, Zandieh MA, Nabavi N, Rabiee N, Ertas YN, Salimimoghadam S, Rashidi M, Rahmanian P, Hushmandi K, Yu W. Chitosan-based nanoscale delivery systems in hepatocellular carcinoma: Versatile bio-platform with theranostic application. Int J Biol Macromol 2023; 242:124935. [PMID: 37230442 DOI: 10.1016/j.ijbiomac.2023.124935] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/13/2023] [Accepted: 05/15/2023] [Indexed: 05/27/2023]
Abstract
The field of nanomedicine has provided a fresh approach to cancer treatment by addressing the limitations of current therapies and offering new perspectives on enhancing patients' prognoses and chances of survival. Chitosan (CS) is isolated from chitin that has been extensively utilized for surface modification and coating of nanocarriers to improve their biocompatibility, cytotoxicity against tumor cells, and stability. HCC is a prevalent kind of liver tumor that cannot be adequately treated with surgical resection in its advanced stages. Furthermore, the development of resistance to chemotherapy and radiotherapy has caused treatment failure. The targeted delivery of drugs and genes can be mediated by nanostructures in treatment of HCC. The current review focuses on the function of CS-based nanostructures in HCC therapy and discusses the newest advances of nanoparticle-mediated treatment of HCC. Nanostructures based on CS have the capacity to escalate the pharmacokinetic profile of both natural and synthetic drugs, thus improving the effectiveness of HCC therapy. Some experiments have displayed that CS nanoparticles can be deployed to co-deliver drugs to disrupt tumorigenesis in a synergistic way. Moreover, the cationic nature of CS makes it a favorable nanocarrier for delivery of genes and plasmids. The use of CS-based nanostructures can be harnessed for phototherapy. Additionally, the incur poration of ligands including arginylglycylaspartic acid (RGD) into CS can elevate the targeted delivery of drugs to HCC cells. Interestingly, smart CS-based nanostructures, including ROS- and pH-sensitive nanoparticles, have been designed to provide cargo release at the tumor site and enhance the potential for HCC suppression.
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Affiliation(s)
- Kimia Karimi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Sarah Mojtabavi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Melina Maghsodlou Nejad
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Aryan Rezaee
- Iran University of Medical Sciences, Tehran, Iran
| | - Shahab Mohtashamian
- Department of Biomedical Engineering, Faculty of Chemical Engineering, Tarbiat Modares University, Tehran, Iran
| | - Erfan Hamedi
- Department of Aquatic Animal Health & Diseases, Department of Clinical Sciences, Faculty of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Farnaz Yousefi
- Department of Clinical Science, Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Farshid Salmani
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Noushin Nabavi
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Navid Rabiee
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA 6150, Australia; School of Engineering, Macquarie University, Sydney, New South Wales 2109, Australia
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, Türkiye
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Parham Rahmanian
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Wei Yu
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China.
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26
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Pimentel JM, Zhou JY, Wu GS. The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer. Cancers (Basel) 2023; 15:2752. [PMID: 37345089 DOI: 10.3390/cancers15102752] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/01/2023] [Accepted: 05/10/2023] [Indexed: 06/23/2023] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that selectively induces apoptosis in tumor cells without harming normal cells, making it an attractive agent for cancer therapy. TRAIL induces apoptosis by binding to and activating its death receptors DR4 and DR5. Several TRAIL-based treatments have been developed, including recombinant forms of TRAIL and its death receptor agonist antibodies, but the efficacy of TRAIL-based therapies in clinical trials is modest. In addition to inducing cancer cell apoptosis, TRAIL is expressed in immune cells and plays a critical role in tumor surveillance. Emerging evidence indicates that the TRAIL pathway may interact with immune checkpoint proteins, including programmed death-ligand 1 (PD-L1), to modulate PD-L1-based tumor immunotherapies. Therefore, understanding the interaction between TRAIL and the immune checkpoint PD-L1 will lead to the development of new strategies to improve TRAIL- and PD-L1-based therapies. This review discusses recent findings on TRAIL-based therapy, resistance, and its involvement in tumor immunosurveillance.
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Affiliation(s)
- Julio M Pimentel
- Molecular Therapeutics Program, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Cancer Biology Program, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Department of Oncology, School of Medicine, Wayne State University, Detroit, MI 48201, USA
| | - Jun-Ying Zhou
- Molecular Therapeutics Program, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Department of Oncology, School of Medicine, Wayne State University, Detroit, MI 48201, USA
| | - Gen Sheng Wu
- Molecular Therapeutics Program, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Cancer Biology Program, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Department of Oncology, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA
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Riera-Domingo C, Leite-Gomes E, Charatsidou I, Zhao P, Carrá G, Cappellesso F, Mourao L, De Schepper M, Liu D, Serneels J, Alameh MG, Shuvaev VV, Geukens T, Isnaldi E, Prenen H, Weissman D, Muzykantov VR, Soenen S, Desmedt C, Scheele CL, Sablina A, Di Matteo M, Martín-Pérez R, Mazzone M. Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding. SCIENCE ADVANCES 2023; 9:eadd5028. [PMID: 36947620 PMCID: PMC10032608 DOI: 10.1126/sciadv.add5028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 02/21/2023] [Indexed: 06/18/2023]
Abstract
Endothelial cells (ECs) grant access of disseminated cancer cells to distant organs. However, the molecular players regulating the activation of quiescent ECs at the premetastatic niche (PMN) remain elusive. Here, we find that ECs at the PMN coexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate death receptor 5 (DR5). Unexpectedly, endothelial TRAIL interacts intracellularly with DR5 to prevent its signaling and preserve a quiescent vascular phenotype. In absence of endothelial TRAIL, DR5 activation induces EC death and nuclear factor κB/p38-dependent EC stickiness, compromising vascular integrity and promoting myeloid cell infiltration, breast cancer cell adhesion, and metastasis. Consistently, both down-regulation of endothelial TRAIL at the PMN by proangiogenic tumor-secreted factors and the presence of the endogenous TRAIL inhibitors decoy receptor 1 (DcR1) and DcR2 favor metastasis. This study discloses an intracrine mechanism whereby TRAIL blocks DR5 signaling in quiescent endothelia, acting as gatekeeper of the vascular barrier that is corrupted by the tumor during cancer cell dissemination.
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Affiliation(s)
- Carla Riera-Domingo
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Eduarda Leite-Gomes
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Iris Charatsidou
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Peihua Zhao
- Laboratory for Mechanisms of Cell Transformation, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory for Mechanisms of Cell Transformation, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Giovanna Carrá
- Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy
- Molecular Biotechnology Center, Torino, Italy
| | - Federica Cappellesso
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Larissa Mourao
- Laboratory for Intravital Imaging and Dynamics of Tumor Progression, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory for Intravital Imaging and Dynamics of Tumor Progression, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Maxim De Schepper
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Dana Liu
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Jens Serneels
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | | | - Vladimir V. Shuvaev
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Tatjana Geukens
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Edoardo Isnaldi
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Hans Prenen
- Department of Oncology, University Hospital Antwerp, Edegem, Belgium
| | - Drew Weissman
- Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USA
| | - Vladimir R. Muzykantov
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Stefaan Soenen
- Leuven Cancer Institute, KU Leuven, Belgium
- NanoHealth and Optical Imaging Group, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Christine Desmedt
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Colinda L. G. J. Scheele
- Laboratory for Intravital Imaging and Dynamics of Tumor Progression, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory for Intravital Imaging and Dynamics of Tumor Progression, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Anna Sablina
- Laboratory for Mechanisms of Cell Transformation, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory for Mechanisms of Cell Transformation, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Mario Di Matteo
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Rosa Martín-Pérez
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
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Evaluation of CDK9 Inhibition by Dinaciclib in Combination with Apoptosis Modulating izTRAIL for the Treatment of Colorectal Cancer. Biomedicines 2023; 11:biomedicines11030928. [PMID: 36979907 PMCID: PMC10045754 DOI: 10.3390/biomedicines11030928] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/19/2023] Open
Abstract
Treatment options for colorectal cancer (CRC), especially in advanced stages are still insufficient. There, the discovery of Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was a bright spot. However, most cancers show resistance toward apoptotic signals. Cyclin-dependent kinase 9 (CDK9) plays a crucial role in cell cycle progression in most tissues. We recently demonstrated the role of CDK9 in mediating TRAIL resistance. In this work, we investigated the role of CDK9 in colorectal cancer. Immunohistochemical analysis of CDK9 expression in cancer and normal tissues of CRC specimens was performed. The effect of selective CDK9 inhibition in combination with TRAIL on CRC cells was analyzed via cell viability, colony formation, and induction of apoptosis by flow cytometry. The mechanism of action was conducted via western blotting. We now have confirmed overexpression of CDK9 in cancer tissues, with low expression associated with poorer survival in a subset of CRC patients. In-vitro, CDK9 inhibition could strongly promote TRAIL-induced cell death in TRAIL-resistant CRC cells. Mechanistically, CDK9 inhibition induced apoptosis by downregulation of antiapoptotic proteins, myeloid leukemia cell differentiation protein 1 (Mcl-1) and FLICE-inhibitory protein (c-FLIP). Overall, we identified CDK9 as a prognostic marker and combined CDK9 inhibition and TRAIL as a novel and promising therapeutic approaches for colorectal cancer.
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Du G, Zhao L, Zheng Y, Belfetmi A, Cai T, Xu B, Heyninck K, Van Den Heede K, Buyse MA, Fontana P, Bowman M, Lin LL, Wu H, Chou JJ. Autoinhibitory structure of preligand association state implicates a new strategy to attain effective DR5 receptor activation. Cell Res 2023; 33:131-146. [PMID: 36604598 PMCID: PMC9892523 DOI: 10.1038/s41422-022-00755-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 11/15/2022] [Indexed: 01/07/2023] Open
Abstract
Members of the tumor necrosis factor receptor superfamily (TNFRSF) are important therapeutic targets that can be activated to induce death of cancer cells or stimulate proliferation of immune cells. Although it has long been implicated that these receptors assemble preligand associated states that are required for dominant interference in human disease, such states have so far eluded structural characterization. Here, we find that the ectodomain of death receptor 5 (DR5-ECD), a representative member of TNFRSF, can specifically self-associate when anchored to lipid bilayer, and we report this self-association structure determined by nuclear magnetic resonance (NMR). Unexpectedly, two non-overlapping interaction interfaces are identified that could propagate to higher-order clusters. Structure-guided mutagenesis indicates that the observed preligand association structure is represented on DR5-expressing cells. The DR5 preligand association serves an autoinhibitory role as single-domain antibodies (sdAbs) that partially dissociate the preligand cluster can sensitize the receptor to its ligand TRAIL and even induce substantial receptor signaling in the absence of TRAIL. Unlike most agonistic antibodies that require multivalent binding to aggregate receptors for activation, these agonistic sdAbs are monovalent and act specifically on an oligomeric, autoinhibitory configuration of the receptor. Our data indicate that receptors such as DR5 can form structurally defined preclusters incompatible with signaling and that true agonists should disrupt the preligand cluster while converting it to signaling-productive cluster. This mechanism enhances our understanding of a long-standing question in TNFRSF signaling and suggests a new opportunity for developing agonistic molecules by targeting receptor preligand clustering.
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Affiliation(s)
- Gang Du
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Linlin Zhao
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yumei Zheng
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Anissa Belfetmi
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Tiantian Cai
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Boying Xu
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | | | | | | | - Pietro Fontana
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Michael Bowman
- Checkpoint Immunology, Immunology & Inflammation, Sanofi, Cambridge, MA, USA
| | - Lih-Ling Lin
- Checkpoint Immunology, Immunology & Inflammation, Sanofi, Cambridge, MA, USA
| | - Hao Wu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
| | - James Jeiwen Chou
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
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Montinaro A, Walczak H. Harnessing TRAIL-induced cell death for cancer therapy: a long walk with thrilling discoveries. Cell Death Differ 2023; 30:237-249. [PMID: 36195672 PMCID: PMC9950482 DOI: 10.1038/s41418-022-01059-z] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 02/10/2023] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) can induce apoptosis in a wide variety of cancer cells, both in vitro and in vivo, importantly without killing any essential normal cells. These findings formed the basis for the development of TRAIL-receptor agonists (TRAs) for cancer therapy. However, clinical trials conducted with different types of TRAs have, thus far, afforded only limited therapeutic benefit, as either the respectively chosen agonist showed insufficient anticancer activity or signs of toxicity, or the right TRAIL-comprising combination therapy was not employed. Therefore, in this review we will discuss molecular determinants of TRAIL resistance, the most promising TRAIL-sensitizing agents discovered to date and, importantly, whether any of these could also prove therapeutically efficacious upon cancer relapse following conventional first-line therapies. We will also discuss the more recent progress made with regards to the clinical development of highly active non-immunogenic next generation TRAs. Based thereupon, we next propose how TRAIL resistance might be successfully overcome, leading to the possible future development of highly potent, cancer-selective combination therapies that are based on our current understanding of biology TRAIL-induced cell death. It is possible that such therapies may offer the opportunity to tackle one of the major current obstacles to effective cancer therapy, namely overcoming chemo- and/or targeted-therapy resistance. Even if this were achievable only for certain types of therapy resistance and only for particular types of cancer, this would be a significant and meaningful achievement.
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Affiliation(s)
- Antonella Montinaro
- Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.
| | - Henning Walczak
- Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.
- CECAD Cluster of Excellence, University of Cologne, 50931, Cologne, Germany.
- Center for Biochemistry, Medical Faculty, Joseph-Stelzmann-Str. 52, University of Cologne, 50931, Cologne, Germany.
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Feng W, Lin H, Rothzerg E, Song D, Zhao W, Ning T, Wei Q, Zhao J, Wood D, Liu Y, Xu J. RNA-seq and Single-Cell Transcriptome Analyses of TRAIL Receptors Gene Expression in Human Osteosarcoma Cells and Tissues. Cancer Inform 2023; 22:11769351231161478. [PMID: 37101729 PMCID: PMC10123892 DOI: 10.1177/11769351231161478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/16/2023] [Indexed: 04/28/2023] Open
Abstract
Osteosarcoma (OS) is the most common primary cancer in the skeletal system, characterized by a high incidence of lung metastasis, local recurrence and death. Systemic treatment of this aggressive cancer has not improved significantly since the introduction of chemotherapy regimens, underscoring a critical need for new treatment strategies. TRAIL receptors have long been proposed to be therapeutic targets for cancer treatment, but their role in osteosarcoma remains unclear. In this study, we investigated the expression profile of four TRAIL receptors in human OS cells using total RNA-seq and single-cell RNA-seq (scRNA-seq). The results revealed that TNFRSF10B and TNFRSF10D but not TNFRSF10A and TNFRSF10C are differentially expressed in human OS cells as compared to normal cells. At the single cell level by scRNA-seq analyses, TNFRSF10B, TNFRSF10D, TNFRSF10A and TNFRSF10C are most abundantly expressed in endothelial cells of OS tissues among nine distinct cell clusters. Notably, in osteoblastic OS cells, TNFRSF10B is most abundantly expressed, followed by TNFRSF10D, TNFRSF10A and TNFRSF10C. Similarly, in an OS cell line U2-OS using RNA-seq, TNFRSF10B is most abundantly expressed, followed by TNFRSF10D, TNFRSF10A and TNFRSF10C. According to the TARGET online database, poor patient outcomes were associated with low expression of TNFRSF10C. These results could provide a new perspective to design novel therapeutic targets of TRAIL receptors for the diagnosis, prognosis and treatment of OS and other cancers.
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Affiliation(s)
- Wenyu Feng
- Department of Orthopaedics, the Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Haiyingjie Lin
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
| | - Emel Rothzerg
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
| | - Dezhi Song
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
- Department of Orthopaedics, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | | | | | - Qingjun Wei
- Department of Orthopaedics, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jinmin Zhao
- Department of Orthopaedics, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - David Wood
- Medical School, The University of Western Australia, Perth, WA, Australia
| | - Yun Liu
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
- Department of Orthopaedics, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jiake Xu
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
- Jiake Xu, School of Biomedical Sciences, The University of Western Australia, 35 Stirling Hwy, Perth, WA 6009, Australia.
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Laudisi F, Pacifico T, Maresca C, Luiz-Ferreira A, Antonelli S, Ortenzi A, Colantoni A, Di Grazia A, Franzè E, Colella M, Di Fusco D, Sica GS, Monteleone I, Monteleone G, Stolfi C. Rafoxanide sensitizes colorectal cancer cells to TRAIL-mediated apoptosis. Biomed Pharmacother 2022; 155:113794. [PMID: 36271571 DOI: 10.1016/j.biopha.2022.113794] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/30/2022] [Accepted: 10/02/2022] [Indexed: 11/24/2022] Open
Abstract
Colorectal cancer (CRC) remains a leading causes of cancer-related death in the world, mainly due to the lack of effective treatment of advanced disease. TNF-related apoptosis-inducing ligand (TRAIL)-driven cell death, a crucial event in the control of tumor growth, selectively targets malignant rather than non-transformed cells. However, the fact that cancer cells, including CRC cells, are either intrinsically resistant or acquire resistance to TRAIL, represents a major hurdle to the use of TRAIL-based strategies in the clinic. Agents able to overcome CRC cell resistance to TRAIL have thus great therapeutic potential and many researchers are making efforts to identify TRAIL sensitizers. The anthelmintic drug rafoxanide has recently emerged as a potent anti-tumor molecule for different cancer types and we recently reported that rafoxanide restrained the proliferation of CRC cells, but not of normal colonic epithelial cells, both in vitro and in a preclinical model mimicking sporadic CRC. As these findings were linked with the induction of endoplasmic reticulum stress, a phenomenon involved in the regulation of various components of the TRAIL-driven apoptotic pathway, we sought to determine whether rafoxanide could restore the sensitivity of CRC cells to TRAIL. Our data show that rafoxanide acts as a selective TRAIL sensitizer in vitro and in a syngeneic experimental model of CRC, by decreasing the levels of c-FLIP and survivin, two key molecules conferring TRAIL resistance. Collectively, our data suggest that rafoxanide could potentially be deployed as an anti-cancer drug in the combinatorial approaches aimed at overcoming CRC cell resistance to TRAIL-based therapies.
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Affiliation(s)
- Federica Laudisi
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Teresa Pacifico
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Claudia Maresca
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Anderson Luiz-Ferreira
- Inflammatory Bowel Disease Research Laboratory, Department of Biological Sciences, Institute of Biotechnology, Federal University of Catalão (UFCAT), Catalão, GO, Brazil
| | - Sara Antonelli
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Angela Ortenzi
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Alfredo Colantoni
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Antonio Di Grazia
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Eleonora Franzè
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Marco Colella
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Davide Di Fusco
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Giuseppe S Sica
- Department of Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Ivan Monteleone
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Carmine Stolfi
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
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Piechna K, Żołyniak A, Jabłońska E, Noyszewska-Kania M, Szydłowski M, Żerek B, Kulecka M, Rumieńczyk I, Mikula M, Juszczyński P. Activity and rational combinations of a novel, engineered chimeric, TRAIL-based ligand in diffuse large B-cell lymphoma. Front Oncol 2022; 12:1048741. [PMID: 36387080 PMCID: PMC9659889 DOI: 10.3389/fonc.2022.1048741] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/13/2022] [Indexed: 11/29/2022] Open
Abstract
Background TRAIL (TNF-related apoptosis inducing ligand) exhibits selective proapoptotic activity in multiple tumor types, while sparing normal cells. This selectivity makes TRAIL an attractive therapeutic candidate. However, despite encouraging activity in preclinical models, clinical trials with TRAIL mimetics/death receptor agonists demonstrated insufficient activity, largely due to emerging resistance to these agents. Herein, we investigated the cytotoxic activity of a novel, TRAIL-based chimeric protein AD-O51.4 combining TRAIL and VEGFA-derived peptide sequences, in hematological malignancies. We characterize key molecular mechanisms leading to resistance and propose rational pharmacological combinations sensitizing cells to AD-O51.4. Methods Sensitivity of DLBCL, classical Hodgkin lymphoma, (cHL), Burkitt lymphoma (BL) and acute myeloid leukemia (AML) to AD-O51.4 was assessed in vitro with MTS assay and apoptosis tests (Annexin V/PI staining). Markers of apoptosis were assessed using immunoblotting, flow cytometry or fluorogenic caspase cleavage assays. Resistant cell lines were obtained by incubation with increasing doses of AD-O51.4. Transcriptomic analyses were performed by RNA sequencing. Sensitizing effects of selected pathway modulators (BCL2, dynamin and HDAC inhibitors) were assessed using MTS/apoptosis assays. Results AD-O51.4 exhibited low-nanomolar cytotoxic activity in DLBCL cells, but not in other lymphoid or AML cell lines. AD-O51.4 induced death-receptor (DR) mediated, caspase-dependent apoptosis in sensitive DLBCL cells, but not in primary resistant cells. The presence of DRs and caspase 8 in cancer cells was crucial for AD-O51.4-induced apoptosis. To understand the potential mechanisms of resistance in an unbiased way, we engineered AD-O51.4-resistant cells and evaluated resistance-associated transcriptomic changes. Resistant cells exhibited changes in the expression of multiple genes and pathways associated with apoptosis, endocytosis and HDAC-dependent epigenetic reprogramming, suggesting potential therapeutic strategies of sensitization to AD-O51.4. In subsequent analyses, we demonstrated that HDAC inhibitors, BCL2 inhibitors and endocytosis/dynamin inhibitors sensitized primary resistant DLBCL cells to AD-O51.4. Conclusions Taken together, we identified rational pharmacologic strategies sensitizing cells to AD-O51.4, including BCL2, histone deacetylase inhibitors and dynamin modulators. Since AD-O51.4 exhibits favorable pharmacokinetics and an acceptable safety profile, its further clinical development is warranted. Identification of resistance mechanisms in a clinical setting might indicate a personalized pharmacological approach to override the resistance.
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Affiliation(s)
- Karolina Piechna
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Aleksandra Żołyniak
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Ewa Jabłońska
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Monika Noyszewska-Kania
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Maciej Szydłowski
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Bartłomiej Żerek
- Department of Drug Discovery, Adamed Pharma S.A. Pienkow, Czosnow, Poland
| | - Maria Kulecka
- Department of Genetics, Maria Sklodowska-Curie National Institute of Oncology, Warsaw, Poland
- Department of Gastroenterology, Hepatology and Clinical Oncology, Centre for Postgraduate Medical Education, Warsaw, Poland
| | - Izabela Rumieńczyk
- Department of Genetics, Maria Sklodowska-Curie National Institute of Oncology, Warsaw, Poland
| | - Michał Mikula
- Department of Genetics, Maria Sklodowska-Curie National Institute of Oncology, Warsaw, Poland
| | - Przemysław Juszczyński
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
- *Correspondence: Przemysław Juszczyński,
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Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells. Cell Death Dis 2022; 13:906. [PMID: 36302756 PMCID: PMC9613879 DOI: 10.1038/s41419-022-05346-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 01/23/2023]
Abstract
Oncogenic transformation leads to changes in glutamine metabolism that make transformed cells highly dependent on glutamine for anabolic growth and survival. Herein, we investigated the cell death mechanism activated in glutamine-addicted tumor cells in response to the limitation of glutamine metabolism. We show that glutamine starvation triggers a FADD and caspase-8-dependent and mitochondria-operated apoptotic program in tumor cells that involves the pro-apoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), but is independent of its cognate ligand TRAIL. In glutamine-depleted tumor cells, activation of the amino acid-sensing general control nonderepressible-2 kinase (GCN2) is responsible for TRAIL-R2 upregulation, caspase-8 activation, and apoptotic cell death. Interestingly, GCN2-dependent ISR signaling induced by methionine starvation also leads to TRAIL-R2 upregulation and apoptosis. Moreover, pharmacological inhibition of transaminases activates a GCN2 and TRAIL-R2-dependent apoptotic mechanism that is inhibited by non-essential amino acids (NEAA). In addition, metabolic stress upon glutamine deprivation also results in GCN2-independent FLICE-inhibitory protein (FLIP) downregulation facilitating caspase-8 activation and apoptosis. Importantly, downregulation of the long FLIP splice form (FLIPL) and apoptosis upon glutamine deprivation are inhibited in the presence of a membrane-permeable α-ketoglutarate. Collectively, our data support a model in which limiting glutamine utilization in glutamine-addicted tumor cells triggers a previously unknown cell death mechanism regulated by GCN2 that involves the TRAIL-R2-mediated activation of the extrinsic apoptotic pathway.
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Jong KXJ, Mohamed EHM, Ibrahim ZA. Escaping cell death via TRAIL decoy receptors: a systematic review of their roles and expressions in colorectal cancer. Apoptosis 2022; 27:787-799. [PMID: 36207556 DOI: 10.1007/s10495-022-01774-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2022] [Indexed: 11/02/2022]
Abstract
The development of targeted therapy such as tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-based therapy has gained increasing attention as a promising new approach in cancer therapy. TRAIL specifically targets cancer cells while sparing the normal cells, thus, limiting the known side effects of the majority anti-cancer therapies. As more extensive research and clinical trials are conducted, resistance to TRAIL molecule has become one of the significant issues associated with the failure of TRAIL in treating colorectal cancer (CRC). To date, the exact mechanism by which TRAIL resistance may have occurred remains unknown. Interestingly, recent studies have revealed the critical role of the TRAIL decoy receptor family; consisting of decoy receptor 1 (DcR1; also known as TRAIL-R3), decoy receptor 2 (DcR2; also known as TRAIL-R4), and osteoprotegerin (OPG) in driving TRAIL resistance. This review highlights the expression of the decoy receptors in CRC and its possible association with the reduction in sensitivity towards TRAIL treatment based on the currently available in vitro, in vivo, and human studies. Additionally, discrepancies between the outcomes from different research groups are discussed, and essential areas are highlighted for future investigation of the roles of decoy receptors in modulating TRAIL-induced apoptosis. Overcoming TRAIL resistance through modulating the expression(s) and elucidating the role(s) of TRAIL decoy receptors hold great promise for TRAIL-based therapies to be extensively explored in treating human cancers including CRC.
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Affiliation(s)
- Kelly Xue Jing Jong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | | | - Zaridatul Aini Ibrahim
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
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Nejabati HR, Roshangar L. Kaempferol: A potential agent in the prevention of colorectal cancer. Physiol Rep 2022; 10:e15488. [PMID: 36259115 PMCID: PMC9579739 DOI: 10.14814/phy2.15488] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 04/18/2023] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer in relation to incidence and mortality rate and its incidence is considerably increasing annually due to the change in the dietary habit and lifestyle of the world population. Although conventional therapeutic options, such as surgery, chemo- and radiotherapy have profound impacts on the treatment of CRC, dietary therapeutic agents, particularly natural products have been regarded as the safest alternatives for the treatment of CRC. Kaempferol (KMP), a naturally derived flavonol, has been shown to reduce the production of reactive oxygen species (ROS), such as superoxide ions, hydroxyl radicals, and reactive nitrogen species (RNS), especially peroxynitrite. Furthermore, this flavonol inhibits xanthine oxidase (XO) activity and increases the activities of catalase, heme oxygenase-1 (HO), and superoxide dismutase (SOD) in a wide range of cancer and non-cancer cells. Based on several studies, KMP is also a hopeful anticancer which carries out its anticancer action via suppression of angiogenesis, stimulation of apoptosis, and cell cycle arrest. Due to various applications of KMP as an anticancer flavonol, this review article aims to highlight the current knowledge regarding the role of KMP in CRC.
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Affiliation(s)
| | - Leila Roshangar
- Stem Cell Research CenterTabriz University of Medical SciencesTabrizIran
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Xia Z, Li M, Hu M, Lin Y, Atteh LL, Fu W, Gao L, Bai M, Huang C, Yue P, Liu Y, Meng W. Phosphoproteomics reveals that cinobufotalin promotes intrahepatic cholangiocarcinoma cell apoptosis by activating the ATM/CHK2/p53 signaling pathway. Front Oncol 2022; 12:982961. [PMID: 36185307 PMCID: PMC9523695 DOI: 10.3389/fonc.2022.982961] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/31/2022] [Indexed: 11/30/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor that originates from bile duct’s epithelial cells and is usually characterized by insidious symptoms and poor prognosis. Cinobufotalin (CB), an active ingredient obtained from the Traditional Chinese Medicine ChanSu, is purported to exhibit a wide range of antitumorigenic activities. However, the mechanism by which it achieves such pharmacological effects remains elusive. Here, we disclosed the mechanism of action by which CB inhibits ICC cells. Initial experiments revealed that the proliferation of RBE and HCCC-9810 cells was significantly inhibited by CB with IC50 values of 0.342 μM and 0.421 μM respectively. CB induced the expression of caspase-3 subsequently leading to the apoptosis of ICC cells. Phosphoproteomics revealed that the phosphorylation of many proteins associated with DNA damage response increased. Kinase-substrate enrichment analysis revealed that ATM was activated after CB treatment, while CDK1 was inactivated. Activated ATM increased p-CHK2-T68 and p-p53-S15, which promoted the expression of FAS, DR4 and DR5 and triggered cell apoptosis. In summary, this work reveals the role of CB in inducing DNA damage and cell apoptosis involved in the activation of the ATM/CHK2/p53 signaling pathway, and indicates that CB may serve as a chemotherapeutic drug candidate for ICC treatment.
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Affiliation(s)
- Zhili Xia
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Minzhen Li
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Meng Hu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Yanyan Lin
- The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Institute of Hepatopancreatobiliary Surgery, Lanzhou, China
| | | | - Wenkang Fu
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Long Gao
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Mingzhen Bai
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Chongfei Huang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Ping Yue
- The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Institute of Hepatopancreatobiliary Surgery, Lanzhou, China
| | - Yu Liu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China
- *Correspondence: Wenbo Meng, ; Yu Liu,
| | - Wenbo Meng
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Institute of Hepatopancreatobiliary Surgery, Lanzhou, China
- *Correspondence: Wenbo Meng, ; Yu Liu,
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Rambow AC, Aschenbach I, Hagelund S, Tawfik D, Gundlach JP, Weiße S, Maass N, Trauzold A. Endogenous TRAIL-R4 critically impacts apoptotic and non-apoptotic TRAIL-induced signaling in cancer cells. Front Cell Dev Biol 2022; 10:942718. [PMID: 36158196 PMCID: PMC9500463 DOI: 10.3389/fcell.2022.942718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/24/2022] [Indexed: 12/02/2022] Open
Abstract
Binding of TRAIL to its death domain-containing receptors TRAIL-R1 and TRAIL-R2 can induce cell death and/or pro-inflammatory signaling. The importance of TRAIL and TRAIL-R1/R2 in tumor immune surveillance and cancer biology has meanwhile been well documented. In addition, TRAIL has been shown to preferentially kill tumor cells, raising hope for the development of targeted anti-cancer therapies. Apart from death-inducing receptors, TRAIL also binds to TRAIL-R3 and TRAIL-R4. Whereas TRAIL-R3 is lacking an intracellular domain entirely, TRAIL-R4 contains a truncated death domain but still a signaling-competent intracellular part. It is assumed that these receptors have anti-apoptotic, yet still not well understood regulatory functions. To analyze the significance of the endogenous levels of TRAIL-R4 for TRAIL-induced signaling in cancer cells, we stably knocked down this receptor in Colo357 and MDA-MB-231 cells and analyzed the activation of apoptotic and non-apoptotic pathways in response to treatment with TRAIL. We found that TRAIL-R4 affects a plethora of signaling pathways, partly in an opposite way. While knockdown of TRAIL-R4 in Colo357 strongly increased apoptosis and reduced clonogenic survival, it inhibited cell death and improved clonogenic survival of MDA-MB-231 cells after TRAIL treatment. Furthermore, TRAIL-R4 turned out to be an important regulator of the expression of a variety of anti-apoptotic proteins in MDA-MB-231 cells since TRAIL-R4-KD reduced the cellular levels of FLIPs, XIAP and cIAP2 but upregulated the levels of Bcl-xL. By inhibiting Bcl-xL with Navitoclax, we could finally show that this protein mainly accounts for the acquired resistance of MDA-MB-231 TRAIL-R4-KD cells to TRAIL-induced apoptosis. Analyses of non-apoptotic signaling pathways revealed that in both cell lines TRAIL-R4-KD resulted in a constitutively increased activity of AKT and ERK, while it reduced AKT activity after TRAIL treatment. Furthermore, TRAIL-R4-KD potentiated TRAIL-induced activation of ERK and p38 in Colo357, and NF-κB in MDA-MB-231 cells. Importantly, in both cell lines the activity of AKT, ERK, p38 and NF-κB after TRAIL treatment was higher in TRAIL-R4-KD cells than in respective control cells. Thus, our data provide evidence for the important regulatory functions of endogenous TRAIL-R4 in cancer cells and improve our understanding of the very complex human TRAIL/TRAIL-R system.
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Affiliation(s)
- Anna-Christina Rambow
- Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany
- Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany
| | - Insa Aschenbach
- Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany
| | - Sofie Hagelund
- Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany
| | - Doaa Tawfik
- Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany
| | - Jan-Paul Gundlach
- Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric-Surgery, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany
| | - Sebastian Weiße
- Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany
| | - Nicolai Maass
- Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany
| | - Anna Trauzold
- Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany
- Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany
- *Correspondence: Anna Trauzold,
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Höfle J, Trenkner T, Kleist N, Schwane V, Vollmers S, Barcelona B, Niehrs A, Fittje P, Huynh‐Tran VH, Sauter J, Schmidt AH, Peine S, Hoelzemer A, Richert L, Altfeld M, Körner C. Engagement of TRAIL triggers degranulation and IFNγ production in human natural killer cells. EMBO Rep 2022; 23:e54133. [PMID: 35758160 PMCID: PMC9346491 DOI: 10.15252/embr.202154133] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 05/16/2022] [Accepted: 05/23/2022] [Indexed: 12/12/2022] Open
Abstract
NK cells utilize a large array of receptors to screen their surroundings for aberrant or virus‐infected cells. Given the vast diversity of receptors expressed on NK cells we seek to identify receptors involved in the recognition of HIV‐1‐infected cells. By combining an unbiased large‐scale screening approach with a functional assay, we identify TRAIL to be associated with NK cell degranulation against HIV‐1‐infected target cells. Further investigating the underlying mechanisms, we demonstrate that TRAIL is able to elicit multiple effector functions in human NK cells independent of receptor‐mediated induction of apoptosis. Direct engagement of TRAIL not only results in degranulation but also IFNγ production. Moreover, TRAIL‐mediated NK cell activation is not limited to its cognate death receptors but also decoy receptor I, adding a new perspective to the perceived regulatory role of decoy receptors in TRAIL‐mediated cytotoxicity. Based on these findings, we propose that TRAIL not only contributes to the anti‐HIV‐1 activity of NK cells but also possesses a multifunctional role beyond receptor‐mediated induction of apoptosis, acting as a regulator for the induction of different effector functions.
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Affiliation(s)
| | | | | | | | | | | | | | - Pia Fittje
- Leibniz Institute of Virology Hamburg Germany
| | - Van Hung Huynh‐Tran
- Inserm, Bordeaux Population Health Research Center UMR1219 and Inria, team SISTM University of Bordeaux Bordeaux France
| | | | | | - Sven Peine
- Institute of Transfusion Medicine University Medical Center Hamburg‐Eppendorf Hamburg Germany
| | - Angelique Hoelzemer
- Leibniz Institute of Virology Hamburg Germany
- German Center for Infection Research (DZIF) Partner Site Hamburg‐Lübeck‐Borstel‐Riems Hamburg Germany
- First Department of Medicine Division of Infectious Diseases University Medical Center Hamburg‐Eppendorf Hamburg Germany
| | - Laura Richert
- Inserm, Bordeaux Population Health Research Center UMR1219 and Inria, team SISTM University of Bordeaux Bordeaux France
| | - Marcus Altfeld
- Leibniz Institute of Virology Hamburg Germany
- Institute of Immunology University Medical Center Hamburg‐Eppendorf Hamburg Germany
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Ferreira A, Pereira F, Reis C, Oliveira MJ, Sousa MJ, Preto A. Crucial Role of Oncogenic KRAS Mutations in Apoptosis and Autophagy Regulation: Therapeutic Implications. Cells 2022; 11:cells11142183. [PMID: 35883626 PMCID: PMC9319879 DOI: 10.3390/cells11142183] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/05/2022] [Accepted: 07/10/2022] [Indexed: 11/16/2022] Open
Abstract
KRAS, one of the RAS protein family members, plays an important role in autophagy and apoptosis, through the regulation of several downstream effectors. In cancer cells, KRAS mutations confer the constitutive activation of this oncogene, stimulating cell proliferation, inducing autophagy, suppressing apoptosis, altering cell metabolism, changing cell motility and invasion and modulating the tumor microenvironment. In order to inhibit apoptosis, these oncogenic mutations were reported to upregulate anti-apoptotic proteins, including Bcl-xL and survivin, and to downregulate proteins related to apoptosis induction, including thymine-DNA glycosylase (TDG) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). In addition, KRAS mutations are known to induce autophagy in order to promote cell survival and tumor progression through MAPK and PI3K regulation. Thus, these mutations confer resistance to anti-cancer drug treatment and, consequently, result in poor prognosis. Several therapies have been developed in order to overcome KRAS-induced cell death resistance and the downstream signaling pathways blockade, especially by combining MAPK and PI3K inhibitors, which demonstrated promising results. Understanding the involvement of KRAS mutations in apoptosis and autophagy regulation, might bring new avenues to the discovery of therapeutic approaches for CRCs harboring KRAS mutations.
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Affiliation(s)
- Anabela Ferreira
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal; (A.F.); (F.P.); (M.J.S.)
- Institute of Science and Innovation for Bio-Sustainability (IB-S), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal
| | - Flávia Pereira
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal; (A.F.); (F.P.); (M.J.S.)
- Institute of Science and Innovation for Bio-Sustainability (IB-S), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; (C.R.); (M.J.O.)
- Institute of Biomedical Engineering (INEB), University of Porto, 4200-135 Porto, Portugal
| | - Celso Reis
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; (C.R.); (M.J.O.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal
| | - Maria José Oliveira
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; (C.R.); (M.J.O.)
- Institute of Biomedical Engineering (INEB), University of Porto, 4200-135 Porto, Portugal
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
| | - Maria João Sousa
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal; (A.F.); (F.P.); (M.J.S.)
- Institute of Science and Innovation for Bio-Sustainability (IB-S), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal
| | - Ana Preto
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal; (A.F.); (F.P.); (M.J.S.)
- Institute of Science and Innovation for Bio-Sustainability (IB-S), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal
- Correspondence: ; Tel.: +351-253-601524
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AF8c, a Multi-Kinase Inhibitor Induces Apoptosis by Activating DR5/Nrf2 via ROS in Colorectal Cancer Cells. Cancers (Basel) 2022; 14:cancers14133043. [PMID: 35804815 PMCID: PMC9264837 DOI: 10.3390/cancers14133043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 06/15/2022] [Accepted: 06/18/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary AF8c, a lapatinib hybrid quinazoline-based EGFR/HER2 inhibitor, was chosen to scrutinize its antiproliferative activity in colorectal cancer (CRC) cells. We found that AF8cinduced apoptosis in CRC cells via diverse mechanisms. In addition to inhibiting the phosphorylation of the ErbB family, AF8c increased the mRNA and protein levels of death receptor 5 (DR5) in vitro and in vivo. In addition, AF8c upregulated several ER stress proteins and the redox-sensitive nuclear respiratory factor 2 alpha subunit (Nrf2) in a p53-dependent manner. We also found that the AF8c-induced increase in the levels of Nrf2, DR5, and apoptosis was diminished by p53 downregulation or knockdown. Furthermore, AF8c showed higher antiproliferative activity than lapatinib in the CRC mouse model in vivo. Therefore, our results suggest AF8c as a highly effective polypharmacological small molecule with an encouraging safety profile, both in vitro and in vivo, for further evaluation as a treatment of CRC. Abstract Our team has previously reported a series of quinazoline-based lapatinib hybrids as potent kinase-targeting anticancer agents. Among them, AF8c showed a relatively safe profile in colorectal cancer (CRC) cells. In this study, we delineate a novel anticancer activity of AF8c in CRC cells. AF8c mediated p53-dependent apoptosis of CRC cells via the generation of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), as well as activation of nuclear respiratory factor 2 alpha subunit (Nrf2) and death receptor 5 (DR5), among others. The silencing of DR5 attenuated the expression levels of Nrf2 and partially inhibited AF8c-induced apoptosis. Additionally, upregulation of Nrf2 by AF8c evoked apoptosis through a decrease in antioxidant levels. Treatment of a CRC mice model with AF8c also resulted in the upregulation of DR5, Nrf2, and CHOP proteins, subsequently leading to a significant decrease in tumor burden. In comparison with lapatinib, AF8c showed higher cellular antiproliferative activity at the tested concentrations in CRC cells and synergized TRAIL effects in CRC cells. Overall, our results suggest that AF8c-induced apoptosis may be associated with DR5/Nrf2 activation through ER stress and ROS generation in CRC cells. These findings indicate that AF8c represents a promising polypharmacological molecule for the treatment of human CRC.
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Induction of DR5-Dependent Apoptosis by PGA 2 through ATF4-CHOP Pathway. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123804. [PMID: 35744931 PMCID: PMC9230093 DOI: 10.3390/molecules27123804] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 06/03/2022] [Accepted: 06/08/2022] [Indexed: 01/01/2023]
Abstract
Prostaglandin (PG) A2, a cyclopentenone PG, induced apoptosis in both HCT116 and HCT116 p53 -/- cells. Although PGA2-induced apoptosis in HCT116 cells was dependent on the p53-DR5 pathway, the mechanism underlying PGA2-induced apoptosis in HCT116 p53 -/- cells remains unknown. In this study, we observed that PGA2 caused an increase of mRNA expression of DR5 and protein expression even in HCT116 p53 -/- cells, accompanied by caspase-dependent apoptosis. Knockdown of DR5 expression by RNA interference inhibited PGA2-induced apoptosis in HCT116 p53 -/- cells. Parallel to the induction of apoptosis, PGA2 treatment upregulated expression of genes upstream of DR5 such as ATF4 and CHOP. Knockdown of CHOP prevented DR5-dependent cell death as well as the expression of DR5 protein. Furthermore, knockdown of ATF4 by RNA interference decreased both mRNA and protein levels of CHOP and DR5, thereby suppressing PGA2-induced cell death. Consistently, the DR5 promoter activity increased by PGA2 was not stimulated when the CHOP binding site in the DR5 promoter was mutated. These results collectively suggest that PGA2 may induce DR5-dependent apoptosis via the ATF4-CHOP pathway in HCT116 p53 null cells.
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43
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Ramírez-Labrada A, Pesini C, Santiago L, Hidalgo S, Calvo-Pérez A, Oñate C, Andrés-Tovar A, Garzón-Tituaña M, Uranga-Murillo I, Arias MA, Galvez EM, Pardo J. All About (NK Cell-Mediated) Death in Two Acts and an Unexpected Encore: Initiation, Execution and Activation of Adaptive Immunity. Front Immunol 2022; 13:896228. [PMID: 35651603 PMCID: PMC9149431 DOI: 10.3389/fimmu.2022.896228] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 04/20/2022] [Indexed: 12/12/2022] Open
Abstract
NK cells are key mediators of immune cell-mediated cytotoxicity toward infected and transformed cells, being one of the main executors of cell death in the immune system. NK cells recognize target cells through an array of inhibitory and activating receptors for endogenous or exogenous pathogen-derived ligands, which together with adhesion molecules form a structure known as immunological synapse that regulates NK cell effector functions. The main and best characterized mechanisms involved in NK cell-mediated cytotoxicity are the granule exocytosis pathway (perforin/granzymes) and the expression of death ligands. These pathways are recognized as activators of different cell death programmes on the target cells leading to their destruction. However, most studies analyzing these pathways have used pure recombinant or native proteins instead of intact NK cells and, thus, extrapolation of the results to NK cell-mediated cell death might be difficult. Specially, since the activation of granule exocytosis and/or death ligands during NK cell-mediated elimination of target cells might be influenced by the stimulus received from target cells and other microenvironment components, which might affect the cell death pathways activated on target cells. Here we will review and discuss the available experimental evidence on how NK cells kill target cells, with a special focus on the different cell death modalities that have been found to be activated during NK cell-mediated cytotoxicity; including apoptosis and more inflammatory pathways like necroptosis and pyroptosis. In light of this new evidence, we will develop the new concept of cell death induced by NK cells as a new regulatory mechanism linking innate immune response with the activation of tumour adaptive T cell responses, which might be the initiating stimulus that trigger the cancer-immunity cycle. The use of the different cell death pathways and the modulation of the tumour cell molecular machinery regulating them might affect not only tumour cell elimination by NK cells but, in addition, the generation of T cell responses against the tumour that would contribute to efficient tumour elimination and generate cancer immune memory preventing potential recurrences.
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Affiliation(s)
- Ariel Ramírez-Labrada
- Immunotherapy, Inflammation and Cancer, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.,Unidad de Nanotoxicología e Inmunotoxicología (UNATI), Centro de Investigación Biomédica de Aragón (CIBA), Aragón Health Research Institute (IIS Aragón), Zaragoza, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Zaragoza, Spain
| | - Cecilia Pesini
- Immunotherapy, Inflammation and Cancer, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Zaragoza, Spain
| | - Llipsy Santiago
- Immunotherapy, Inflammation and Cancer, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.,Instituto de Carboquimica (ICB), CSIC, Zaragoza, Spain
| | - Sandra Hidalgo
- Immunotherapy, Inflammation and Cancer, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Zaragoza, Spain
| | - Adanays Calvo-Pérez
- Immunotherapy, Inflammation and Cancer, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Zaragoza, Spain
| | - Carmen Oñate
- Immunotherapy, Inflammation and Cancer, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Zaragoza, Spain
| | - Alejandro Andrés-Tovar
- Immunotherapy, Inflammation and Cancer, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain
| | - Marcela Garzón-Tituaña
- Immunotherapy, Inflammation and Cancer, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Zaragoza, Spain
| | - Iratxe Uranga-Murillo
- Immunotherapy, Inflammation and Cancer, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Zaragoza, Spain
| | - Maykel A Arias
- Immunotherapy, Inflammation and Cancer, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Zaragoza, Spain
| | - Eva M Galvez
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Zaragoza, Spain.,Instituto de Carboquimica (ICB), CSIC, Zaragoza, Spain
| | - Julián Pardo
- Immunotherapy, Inflammation and Cancer, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Zaragoza, Spain.,Department of Microbiology, Preventive Medicine and Public Health, Fundación Agencia Aragonesa para la Investigación y el Desarrollo ARAID Foundation, University of Zaragoza, Zaragoza, Spain
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Deep exploration of immune function in EGFR wild-type and mutated lung adenocarcinomas by gene expression profiling: role of TRAIL-R2 (TNFRSF10B) in patient treatment and outcome. Hum Pathol 2022; 126:9-18. [PMID: 35550831 DOI: 10.1016/j.humpath.2022.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/28/2022] [Accepted: 05/03/2022] [Indexed: 11/20/2022]
Abstract
The tumor microenvironment is important in the initiation and progression of lung adenocarcinoma (LUAD). In this study, we aim to analyze the expression profile of immune-related genes in LUADs, examine the differential expression of immune-related genes in epidermal growth factor receptor (EGFR) wild-type and mutant LUADs, and the clinicopathologic significance of these differentially expressed genes. We used the NanoString PanCancer Immune Profiling Panel to examine 34 cases of LUADs (18 EGFR wild-type, 16 EGFR mutant). In EGFR wild-type LUADs, the macrophage and neutrophil signatures are significantly higher, and significantly higher expression of chemokines, interleukins, leukocyte, macrophage, natural killer cell, pathogen defense, Tumor necrosis factor superfamily, and transporter function signatures are also observed. TNFRSF10B mRNA was preferentially expressed in EGFR wild-type LUADs (p = 6.15e-6, adjusted p = 0.0244). Immunohistochemical staining for TRAIL-R2 (encoded by TNFRSF10B) on 134 tissue microarray LUAD cases demonstrated strong, moderate, and weak staining in 75 (56.0%), 46 (34.3%), and 13 (9.7%) cases, respectively. Strong TRAIL-R2 expression was significantly associated with poor overall survival (OS) in all stages and EGFR wild-type LUADs, but not in EGFR-mutant tumors. Furthermore, strong TRAIL-R2 expression (p = 0.004) was an independent risk factor for poor OS. In summary, TNFRSF10B mRNA revealed significantly higher expression in EGFR wild-type LUADs, and strong TRAIL-R2 expression predicts an unfavorable prognosis for these tumors. These patients may benefit from additional treatment with TRAIL-R2 targeted therapies.
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Koliaki C, Katsilambros N. Repositioning the Role of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) on the TRAIL to the Development of Diabetes Mellitus: An Update of Experimental and Clinical Evidence. Int J Mol Sci 2022; 23:ijms23063225. [PMID: 35328646 PMCID: PMC8949963 DOI: 10.3390/ijms23063225] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 01/25/2023] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF protein superfamily, represents a multifaceted cytokine with unique biological features including both proapoptotic and pro-survival effects in different cell types depending on receptor interactions and local stimuli. Beyond its extensively studied anti-tumor and immunomodulatory properties, a growing body of experimental and clinical evidence over the past two decades suggests a protective role of TRAIL in the development of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. This evidence can be briefly summarized by the following observations: (i) acceleration and exacerbation of T1DM and T2DM by TRAIL blockade or genetic deficiency in animal models, (ii) prevention and amelioration of T1DM and T2DM with recombinant TRAIL treatment or systemic TRAIL gene delivery in animal models, (iii) significantly reduced circulating soluble TRAIL levels in patients with T1DM and T2DM both at disease onset and in more advanced stages of diabetes-related complications such as cardiovascular disease and diabetic nephropathy, (iv) increase of serum TRAIL levels in diabetic patients after initiation of antidiabetic treatment and metabolic improvement. To explore the underlying mechanisms and provide mechanistic links between TRAIL and diabetes, a number of animal and in vitro studies have reported direct effects of TRAIL on several tissues involved in diabetes pathophysiology such as pancreatic islets, skeletal muscle, adipose tissue, liver, kidney, and immune and vascular cells. Residual controversy remains regarding the effects of TRAIL on adipose tissue homeostasis. Although the existing evidence is encouraging and paves the way for investigating TRAIL-related interventions in diabetic patients with cardiometabolic abnormalities, caution is warranted in the extrapolation of animal and in vitro data to the clinical setting, and further research in humans is imperative in order to uncover all aspects of the TRAIL-diabetes relationship and delineate its therapeutic implications in metabolic disease.
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Jing Y, Liang W, Zhang L, Tang J, Huang Z. The Role of Mesenchymal Stem Cells in the Induction of Cancer-Stem Cell Phenotype. Front Oncol 2022; 12:817971. [PMID: 35251985 PMCID: PMC8891610 DOI: 10.3389/fonc.2022.817971] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/19/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) modify and form their microenvironment by recruiting and activating specific cell types such as mesenchymal stem cells (MSCs). Tumor-infiltrating MSCs help to establish a suitable tumor microenvironment for the restoration of CSCs and tumor progression. In addition, crosstalk between cancer cells and MSCs in the microenvironment induces a CSC phenotype in cancer cells. Many mechanisms are involved in crosstalk between CSCs/cancer cells and MSCs including cell-cell interaction, secretion of exosomes, and paracrine secretion of several molecules including inflammatory mediators, cytokines, and growth factors. Since this crosstalk may contribute to drug resistance, metastasis, and tumor growth, it is suggested that blockade of the crosstalk between MSCs and CSCs/cancer cells can provide a new avenue to improving the cancer therapeutic tools. In this review, we will discuss the role of MSCs in the induction of cancer stem cell phenotype and the restoration of CSCs. We also discuss targeting the crosstalk between MSCs and CSCs/cancer cells as a therapeutic strategy.
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Affiliation(s)
- Yuanming Jing
- Department of Gastrointestinal Surgery, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Wenqing Liang
- Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Lin Zhang
- Department of Pharmacy, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Junjun Tang
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Zongliang Huang, ; Junjun Tang ,
| | - Zongliang Huang
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Zongliang Huang, ; Junjun Tang ,
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Abstract
PURPOSE OF REVIEW Apoptosis is a major mechanism of cancer cell death. Thus, evasion of apoptosis results in therapy resistance. Here, we review apoptosis modulators in cancer and their recent developments, including MDM2 inhibitors and kinase inhibitors that can induce effective apoptosis. RECENT FINDINGS Both extrinsic pathways (external stimuli through cell surface death receptor) and intrinsic pathways (mitochondrial-mediated regulation upon genotoxic stress) regulate the complex process of apoptosis through orchestration of various proteins such as members of the BCL-2 family. Dysregulation within these complex steps can result in evasion of apoptosis. However, via the combined evolution of medicinal chemistry and molecular biology, omics assays have led to innovative inducers of apoptosis and inhibitors of anti-apoptotic regulators. Many of these agents are now being tested in cancer patients in early-phase trials. We believe that despite a sluggish speed of development, apoptosis targeting holds promise as a relevant strategy in cancer therapeutics.
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Urine proteomics as a non-invasive approach to monitor exertional rhabdomyolysis during military training. J Proteomics 2022; 258:104498. [DOI: 10.1016/j.jprot.2022.104498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 01/21/2022] [Indexed: 11/23/2022]
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Granqvist V, Holmgren C, Larsson C. The combination of TRAIL and the Smac mimetic LCL-161 induces an irreversible phenotypic change of MCF-7 breast cancer cells. Exp Mol Pathol 2022; 125:104739. [PMID: 35007560 DOI: 10.1016/j.yexmp.2021.104739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 11/22/2021] [Accepted: 12/28/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Breast cancer is the most common malignancy affecting women. Although the prognosis generally is good, a substantial number of patients still suffer from relapse, emphasizing the need for novel treatments. Smac mimetics were developed to facilitate cell death by blocking inhibitor of apoptosis proteins (IAPs). It has been suggested that TNF-related apoptosis inducing ligand (TRAIL) can be used together with Smac mimetics to induce cancer cell death. METHODS Cell viability was studied with Trypan blue staining and Annexin V assay, siRNA was used to downregulate specific proteins, protein levels were estimated with Western blot, and mRNA levels were analyzed with qPCR, microarray and RNA-seq. For global expression, groups were compared with principal component analysis and the limma package in R. Gene enrichment was analyzed with Fisher's test. For other experiments, significance of difference was tested by one-way ANOVA, followed by Tukey's HSD test. RESULTS The combination of Smac mimetic LCL-161 and TRAIL induces an irreversible change in phenotype, but not cell death, of luminal MCF-7 breast cancer cells. The cells become small and circular and dissociate from each other and the effect could not be reversed by returning the cells to regular growth medium. The morphology change could be prevented by caspase inhibition using z-VAD-FMK and downregulation of caspase-8. Caspase-7 is also indicated to be of importance since downregulation of this caspase resulted in fewer morphologically changed cells. Enrichment analyses of changes in global gene expression demonstrated that genes associated with estrogen receptor (ER) signaling are downregulated, whereas nuclear factor kappa B- (NF-κB) and interferon- (IFN) driven genes are upregulated in altered cells. However, inhibition of these pathways did not influence the change in morphology. Induction of IFN-induced genes were potentiated but NF-ĸB-driven genes were slightly suppressed by caspase inhibition. CONCLUSIONS The results demonstrate that LCL-161 and TRAIL can irreversibly alter the MCF-7 breast cancer cell phenotype. However, the changes in morphology and global gene expression are mediated via separate pathways.
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Affiliation(s)
- Victoria Granqvist
- Lund University, Translational Cancer Research, Medicon Village, Lund, Sweden
| | - Christian Holmgren
- Lund University, Translational Cancer Research, Medicon Village, Lund, Sweden
| | - Christer Larsson
- Lund University, Translational Cancer Research, Medicon Village, Lund, Sweden.
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Wang BT, Kothambawala T, Wang L, Matthew TJ, Calhoun SE, Saini AK, Kotturi MF, Hernandez G, Humke EW, Peterson MS, Sinclair AM, Keyt BA. Multimeric Anti-DR5 IgM Agonist Antibody IGM-8444 Is a Potent Inducer of Cancer Cell Apoptosis and Synergizes with Chemotherapy and BCL-2 Inhibitor ABT-199. Mol Cancer Ther 2021; 20:2483-2494. [PMID: 34711645 PMCID: PMC9398157 DOI: 10.1158/1535-7163.mct-20-1132] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 07/07/2021] [Accepted: 09/15/2021] [Indexed: 01/07/2023]
Abstract
Death receptor 5 (DR5) is an attractive target for cancer therapy due to its broad upregulated expression in multiple cancers and ability to directly induce apoptosis. Though anti-DR5 IgG antibodies have been evaluated in clinical trials, limited efficacy has been attributed to insufficient receptor crosslinking. IGM-8444 is an engineered, multivalent agonistic IgM antibody with 10 binding sites to DR5 that induces cancer cell apoptosis through efficient DR5 multimerization. IGM-8444 bound to DR5 with high avidity and was substantially more potent than an IgG with the same binding domains. IGM-8444 induced cytotoxicity in a broad panel of solid and hematologic cancer cell lines but did not kill primary human hepatocytes in vitro, a potential toxicity of DR5 agonists. In multiple xenograft tumor models, IGM-8444 monotherapy inhibited tumor growth, with strong and sustained tumor regression observed in a gastric PDX model. When combined with chemotherapy or the BCL-2 inhibitor ABT-199, IGM-8444 exhibited synergistic in vitro tumor cytotoxicity and enhanced in vivo efficacy, without augmenting in vitro hepatotoxicity. These results support the clinical development of IGM-8444 in solid and hematologic malignancies as a monotherapy and in combination with chemotherapy or BCL-2 inhibition.
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Affiliation(s)
| | | | - Ling Wang
- IGM Biosciences Inc., Mountain View, California
| | | | | | | | | | | | | | | | | | - Bruce A Keyt
- IGM Biosciences Inc., Mountain View, California.
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