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Zhang P, Wang W, Xiang H, Zhou Y, Peng Q, Liu G, Xu ZX, Lu L. DAZAP1 maintains gastric cancer stemness by inducing mitophagy. JCI Insight 2025; 10:e175422. [PMID: 40401521 DOI: 10.1172/jci.insight.175422] [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: 09/01/2023] [Accepted: 04/02/2025] [Indexed: 05/23/2025] Open
Abstract
Stem cells play a pivotal role in the malignant behavior of gastric cancer (GC), complicating its treatment and prognosis. However, the regulatory mechanisms of GC stem cells (GCSCs) remain poorly understood. DAZ-associated protein 1 (DAZAP1), a splicing regulator linked to various malignancies, has an unclear role in GC. This study investigated DAZAP1's impact on GC stemness and its mechanisms. DAZAP1 promoted tumor progression in GCSCs, as shown by sphere formation assays and stemness marker analysis. Functional enrichment analysis suggested that DAZAP1 enhanced tumor stemness by promoting oxidative phosphorylation (OXPHOS), which was validated through Seahorse assays and measurements of mitochondrial potential. Transmission electron microscopy and immunofluorescence analyses demonstrated that DAZAP1 promoted mitophagy. RNA immunoprecipitation and PCR analysis revealed that DAZAP1 regulated the splicing and expression of the mitophagy-related gene ULK1 through nonsense-mediated mRNA decay. Rescue experiments showed that overexpression of ULK1 reversed the suppression of GC stemness and OXPHOS levels induced by DAZAP1 silencing. Our findings indicate that DAZAP1 reduces ULK1 decay, thereby activating mitophagy and enhancing OXPHOS to fulfill the metabolic demands of cancer stem cells. These findings highlight the therapeutic potential of DAZAP1 as a target for treating GC.
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Affiliation(s)
- Peiling Zhang
- Department of Medical Oncology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
- Department of Medical Oncology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Wei Wang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Hong Xiang
- Department of Medical Oncology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Yun Zhou
- Department of Medical Oncology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Qian Peng
- Department of Medical Oncology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Guolong Liu
- Department of Medical Oncology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
- Department of Medical Oncology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhi-Xiang Xu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Lin Lu
- Department of Medical Oncology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
- Department of Medical Oncology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
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2
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Higuchi Y, Teo JL, Yi D, Kahn M. Safely Targeting Cancer, the Wound That Never Heals, Utilizing CBP/Beta-Catenin Antagonists. Cancers (Basel) 2025; 17:1503. [PMID: 40361430 PMCID: PMC12071182 DOI: 10.3390/cancers17091503] [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: 03/25/2025] [Revised: 04/25/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025] Open
Abstract
Stem cells, both normal somatic (SSC) and cancer stem cells (CSC) exist in minimally two states, i.e., quiescent and activated. Regulation of these two states, including their reliance on different metabolic processes, i.e., FAO and glycolysis in quiescent versus activated stem cells respectively, involves the analysis of a complex array of factors (nutrient and oxygen levels, adhesion molecules, cytokines, etc.) to initiate the epigenetic changes to either depart or enter quiescence. Quiescence is a critical feature of SSC that is required to maintain the genomic integrity of the stem cell pool, particularly in long lived complex organisms. Quiescence in CSC, whether they are derived from mutations arising in SSC, aberrant microenvironmental regulation, or via dedifferentiation of more committed progenitors, is a critical component of therapy resistance and disease latency and relapse. At the beginning of vertebrate evolution, approximately 450 million years ago, a gene duplication generated the two members of the Kat3 family, CREBBP (CBP) and EP300 (p300). Despite their very high degree of homology, these two Kat3 coactivators play critical and non-redundant roles at enhancers and super-enhancers via acetylation of H3K27, thereby controlling stem cell quiescence versus activation and the cells metabolic requirements. In this review/perspective, we discuss the unique regulatory roles of CBP and p300 and how specifically targeting the CBP/β-catenin interaction utilizing small molecule antagonists, can correct lineage infidelity and safely eliminate quiescent CSC.
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Affiliation(s)
- Yusuke Higuchi
- Beckman Research Institute, City of Hope, Duarte, CA 91010, USA;
| | - Jia-Ling Teo
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; (J.-L.T.); (D.Y.)
| | - Daniel Yi
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; (J.-L.T.); (D.Y.)
| | - Michael Kahn
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; (J.-L.T.); (D.Y.)
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Petrova B, Guler AT. Recent Developments in Single-Cell Metabolomics by Mass Spectrometry─A Perspective. J Proteome Res 2025; 24:1493-1518. [PMID: 39437423 PMCID: PMC11976873 DOI: 10.1021/acs.jproteome.4c00646] [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: 07/28/2024] [Revised: 10/07/2024] [Accepted: 10/15/2024] [Indexed: 10/25/2024]
Abstract
Recent advancements in single-cell (sc) resolution analyses, particularly in sc transcriptomics and sc proteomics, have revolutionized our ability to probe and understand cellular heterogeneity. The study of metabolism through small molecules, metabolomics, provides an additional level of information otherwise unattainable by transcriptomics or proteomics by shedding light on the metabolic pathways that translate gene expression into functional outcomes. Metabolic heterogeneity, critical in health and disease, impacts developmental outcomes, disease progression, and treatment responses. However, dedicated approaches probing the sc metabolome have not reached the maturity of other sc omics technologies. Over the past decade, innovations in sc metabolomics have addressed some of the practical limitations, including cell isolation, signal sensitivity, and throughput. To fully exploit their potential in biological research, however, remaining challenges must be thoroughly addressed. Additionally, integrating sc metabolomics with orthogonal sc techniques will be required to validate relevant results and gain systems-level understanding. This perspective offers a broad-stroke overview of recent mass spectrometry (MS)-based sc metabolomics advancements, focusing on ongoing challenges from a biologist's viewpoint, aimed at addressing pertinent and innovative biological questions. Additionally, we emphasize the use of orthogonal approaches and showcase biological systems that these sophisticated methodologies are apt to explore.
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Affiliation(s)
- Boryana Petrova
- Medical
University of Vienna, Vienna 1090, Austria
- Department
of Pathology, Boston Children’s Hospital, Boston, Massachusetts 02115, United States
| | - Arzu Tugce Guler
- Department
of Pathology, Boston Children’s Hospital, Boston, Massachusetts 02115, United States
- Institute
for Experiential AI, Northeastern University, Boston, Massachusetts 02115, United States
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4
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Selvaraj NR, Nandan D, Nair BG, Nair VA, Venugopal P, Aradhya R. Oxidative Stress and Redox Imbalance: Common Mechanisms in Cancer Stem Cells and Neurodegenerative Diseases. Cells 2025; 14:511. [PMID: 40214466 PMCID: PMC11988017 DOI: 10.3390/cells14070511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 02/21/2025] [Accepted: 02/25/2025] [Indexed: 04/14/2025] Open
Abstract
Oxidative stress (OS) is an established hallmark of cancer and neurodegenerative disorders (NDDs), which contributes to genomic instability and neuronal loss. This review explores the contrasting role of OS in cancer stem cells (CSCs) and NDDs. Elevated levels of reactive oxygen species (ROS) contribute to genomic instability and promote tumor initiation and progression in CSCs, while in NDDs such as Alzheimer's and Parkinson's disease, OS accelerates neuronal death and impairs cellular repair mechanisms. Both scenarios involve disruption of the delicate balance between pro-oxidant and antioxidant systems, which leads to chronic oxidative stress. Notably, CSCs and neurons display alterations in redox-sensitive signaling pathways, including Nrf2 and NF-κB, which influence cell survival, proliferation, and differentiation. Mitochondrial dynamics further illustrate these differences: enhanced function in CSCs supports adaptability and survival, whereas impairments in neurons heighten vulnerability. Understanding these common mechanisms of OS-induced redox imbalance may provide insights for developing interventions, addressing aging hallmarks, and potentially mitigating or preventing both cancer and NDDs.
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Affiliation(s)
| | | | | | | | - Parvathy Venugopal
- School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 690525, Kerala, India; (N.R.S.); (D.N.); (B.G.N.); (V.A.N.)
| | - Rajaguru Aradhya
- School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 690525, Kerala, India; (N.R.S.); (D.N.); (B.G.N.); (V.A.N.)
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Jan A, Sofi S, Jan N, Mir MA. An update on cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer. Future Oncol 2025; 21:715-735. [PMID: 39936282 PMCID: PMC11881842 DOI: 10.1080/14796694.2025.2461443] [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: 10/29/2024] [Accepted: 01/29/2025] [Indexed: 02/13/2025] Open
Abstract
Triple-negative breast cancer (TNBC) presents a formidable global health challenge, marked by its aggressive behavior and significant treatment resistance. This subtype, devoid of estrogen, progesterone, and HER2 receptors, largely relies on breast cancer stem cells (BCSCs) for its progression, metastasis, and recurrence. BCSCs, characterized by their self-renewal capacity and resistance to conventional therapies, exploit key surface markers and critical signaling pathways like Wnt, Hedgehog, Notch, TGF-β, PI3K/AKT/mTOR and Hippo-YAP/TAZ to thrive. Their adaptability is underscored by mechanisms including drug efflux and enhanced DNA repair, contributing to poor prognosis and high recurrence rates. The tumor microenvironment (TME) further facilitates BCSC survival through complex interactions with stromal and immune cells. Emerging therapeutic strategies targeting BCSCs - ranging from immunotherapy and nanoparticle-based drug delivery systems to gene-editing technologies - aim to disrupt these resistant cells. Additionally, innovative approaches focusing on exosome-mediated signaling and metabolic reprogramming show promise in overcoming chemoresistance. By elucidating the distinct characteristics of BCSCs and their role in TNBC, researchers are paving the way for novel treatments that may effectively eradicate these resilient cells, mitigate metastasis, and ultimately improve patient outcomes. This review highlights the urgent need for targeted strategies that address the unique biology of BCSCs in the pursuit of more effective therapeutic interventions for TNBC.
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Affiliation(s)
- Asma Jan
- Cancer Biology Laboratory, Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Shazia Sofi
- Cancer Biology Laboratory, Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Nusrat Jan
- Cancer Biology Laboratory, Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Manzoor Ahmad Mir
- Cancer Biology Laboratory, Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
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Wang J, Liu L, Gao X, Liu X, Dai Y, Mao Z, Huang S, Li J, Wang D, Qi Y, Han Y, Xu Y, Chua CYX, Grattoni A, Xie W, Yang H, Huang G. A novel pathway for stemness propagation and chemoresistance in non-small cell lung cancer via phosphorylated PKM2-loaded small extracellular vesicles. Theranostics 2025; 15:3439-3461. [PMID: 40093893 PMCID: PMC11905138 DOI: 10.7150/thno.103722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 02/11/2025] [Indexed: 03/19/2025] Open
Abstract
Rationale: Non-small cell lung cancer (NSCLC) is a predominant cause of cancer-related mortality, with its progression and treatment resistance significantly influenced by cancer stem cells (CSCs) and their complex intercellular communication mechanisms. Small extracellular vesicles (sEVs) have emerged as pivotal mediators of intercellular signaling, affecting tumor microenvironment modulation and therapeutic resistance. This study investigates the role of CSC-derived sEVs in transmitting stemness traits through the selective sorting of pyruvate kinase M2 phosphorylated at the Y105 site (pY105-PKM2), mediated by the adaptor protein IQGAP1, which supports CSC maintenance and drug resistance in NSCLC. Methods: In vitro and in vivo experiments, including proteomic and transcriptomic analyses, were conducted to identify key regulators of sEV-mediated signaling. Immunoprecipitation, proximity ligation assays, and immunofluorescence were used to examine the role of IQGAP1 in the sorting of pY105-PKM2 into sEVs. Functional assays, including sphere formation, chemoresistance tests, metabolic assessments, and cell cycle analysis, were conducted to evaluate the effects of sEV-mediated delivery of pY105-PKM2 on recipient cells. Additionally, immunohistochemistry and survival analysis were performed on tumor samples from NSCLC patients to establish clinical correlations. Results: We unveiled a novel mechanism by which CSC-derived sEVs transmit stemness traits to replenish the CSC pool in NSCLC. CSC-derived sEVs were enriched with pY105-PKM2, correlating with enhanced stemness, chemoresistance, and poor clinical outcomes. Mechanistically, IQGAP1 was identified as an adaptor facilitating the selective sorting of pY105-PKM2 into sEVs through interactions with the ESCRT component TSG101. Recipient cells treated with CSC-derived sEVs exhibited metabolic reprogramming, slower cell cycle progression, and enhanced chemoresistance. The synergistic role of IQGAP1 and pY105-PKM2 was confirmed, highlighting their critical contributions to CSC maintenance and malignant progression. Conclusion: This study highlights the critical role of CSC-derived sEVs in NSCLC progression and therapy resistance through the IQGAP1-mediated selective sorting of pY105-PKM2. By uncovering this novel pathway, our findings provide valuable insights into CSC pool replenishment and therapeutic resistance mechanisms in NSCLC, identifying IQGAP1 and pY105-PKM2 as promising therapeutic targets for mitigating CSC-driven malignancy and enhancing treatment efficacy.
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Affiliation(s)
- Jingyi Wang
- Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Liu Liu
- Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xinyu Gao
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Xiyu Liu
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Yitian Dai
- Laboratory of Stem Cell Biology and Engineering, New York Blood Center, New York, NY 10065, USA
| | - Zijun Mao
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Shengzhe Huang
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Junjian Li
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Dongliang Wang
- Department of Nuclear Medicine, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Yu Qi
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Yingwen Han
- Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yunjing Xu
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Corrine Ying Xuan Chua
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Alessandro Grattoni
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Wenhui Xie
- Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hao Yang
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Gang Huang
- Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
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Liu Y, Sun X, Wei C, Guo S, Song C, Zhang J, Bai J. Targeted Drug Nanodelivery and Immunotherapy for Combating Tumor Resistance. Comb Chem High Throughput Screen 2025; 28:561-581. [PMID: 38676501 DOI: 10.2174/0113862073296206240416060154] [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: 12/27/2023] [Revised: 03/05/2024] [Accepted: 03/09/2024] [Indexed: 04/29/2024]
Abstract
Chemotherapy resistance is a common cause of tumor treatment failure. Various molecular responses, such as increased expression of efflux transporter proteins, including Pglycoprotein (P-gp), changes in the tumor microenvironment (TME), the role of platelets, and the effects of cancer stem cells (CSCs), can lead to drug resistance. Through extensive research on the mechanisms of drug resistance, more effective anti-resistance drugs and therapeutic approaches are being developed. This review explores drug resistance mechanisms and summarizes relevant anti-resistance drugs. In addition, due to the therapeutic limitations of the aforementioned treatments, new advances in nanocarrier-based combination immunotherapy to address the challenge of drug resistance have been described. Nanocarriers combined with immunotherapy can not only target tumor sites for targeted drug release but also modulate the autoimmune system and enhance immune efficacy, thereby overcoming tumor drug resistance. This review suggests new strategies for overcoming tumor drug resistance and is expected to inform tumor treatment and prognosis.
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Affiliation(s)
- Yun Liu
- School of Stomatology, Shandong Second Medical University, Weifang, 261053, China
| | - Xinyu Sun
- School of Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Chen Wei
- School of Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Shoudong Guo
- School of Pharmacy, Shandong Second Medical University, Weifang, 261053, China
| | - Chunxiao Song
- Anorectal Department, Weifang people's Hospital, Weifang, 261000, China
| | - Jiangyu Zhang
- school of Chemistry and Chemical Engineering, Xingtai University, Xingtai, 054001, China
| | - Jingkun Bai
- School of Bioscience and Technology, Shandong Second Medical University, Weifang, 261053, China
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8
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Kong W, Gao Y, Zhao S, Yang H. Cancer stem cells: advances in the glucose, lipid and amino acid metabolism. Mol Cell Biochem 2024; 479:2545-2563. [PMID: 37882986 DOI: 10.1007/s11010-023-04861-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 09/13/2023] [Indexed: 10/27/2023]
Abstract
Cancer stem cells (CSCs) are a class of cells with self-renewal and multi-directional differentiation potential, which are present in most tumors, particularly in aggressive tumors, and perform a pivotal role in recurrence and metastasis and are expected to be one of the important targets for tumor therapy. Studies of tumor metabolism in recent years have found that the metabolic characteristics of CSCs are distinct from those of differentiated tumor cells, which are unique to CSCs and contribute to the maintenance of the stemness characteristics of CSCs. Moreover, these altered metabolic profiles can drive the transformation between CSCs and non-CSCs, implying that these metabolic alterations are important markers for CSCs to play their biological roles. The identification of metabolic changes in CSCs and their metabolic plasticity mechanisms may provide some new opportunities for tumor therapy. In this paper, we review the metabolism-related mechanisms of CSCs in order to provide a theoretical basis for their potential application in tumor therapy.
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Affiliation(s)
- Weina Kong
- Department of Obstetrics and Gynecology, Xijing Hospital, Air Forth Military Medical University, 127 Changle West Road, Xincheng District, Xi'an City, Shaanxi Province, China
| | - Yunge Gao
- Department of Obstetrics and Gynecology, Xijing Hospital, Air Forth Military Medical University, 127 Changle West Road, Xincheng District, Xi'an City, Shaanxi Province, China
| | - Shuhua Zhao
- Department of Obstetrics and Gynecology, Xijing Hospital, Air Forth Military Medical University, 127 Changle West Road, Xincheng District, Xi'an City, Shaanxi Province, China
| | - Hong Yang
- Department of Obstetrics and Gynecology, Xijing Hospital, Air Forth Military Medical University, 127 Changle West Road, Xincheng District, Xi'an City, Shaanxi Province, China.
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9
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Hsu MC. Editorial: Breakthroughs in tumor stem cell research. Front Cell Dev Biol 2024; 12:1492867. [PMID: 39398479 PMCID: PMC11467216 DOI: 10.3389/fcell.2024.1492867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 09/11/2024] [Indexed: 10/15/2024] Open
Affiliation(s)
- Ming-Chuan Hsu
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
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10
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Liu YJ, Li JX, Li JP, Hu YD, Ma ZB, Huang W, Liu SL, Zou X. Endoplasmic Reticulum Membrane Protein Complex Regulates Cancer Stem Cells and is Associated with Sorafenib Resistance in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2024; 11:1519-1539. [PMID: 39139735 PMCID: PMC11321348 DOI: 10.2147/jhc.s474343] [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: 04/17/2024] [Accepted: 08/01/2024] [Indexed: 08/15/2024] Open
Abstract
Background Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential. Methods Publicly available sequencing data and biopsy specimens were analyzed to assess EMC's clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle. Results EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells' sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1's role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation. Conclusion EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy.
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Affiliation(s)
- Yuan-Jie Liu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
| | - Jing-Xiao Li
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
| | - Jie-Pin Li
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
| | - Yi-Dou Hu
- Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People’s Republic of China
| | - Zhi-Bin Ma
- Nanjing YOUMENG Biology Science and Technology Co. Ltd, Nanjing, Jiangsu, 210029, People’s Republic of China
| | - Wei Huang
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
| | - Shen-Lin Liu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
| | - Xi Zou
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
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11
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Kovale L, Singh MK, Kim J, Ha J. Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer. Int J Mol Sci 2024; 25:8647. [PMID: 39201332 PMCID: PMC11354724 DOI: 10.3390/ijms25168647] [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: 06/11/2024] [Revised: 07/30/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
Cancer stem cells represent a resilient subset within the tumor microenvironment capable of differentiation, regeneration, and resistance to chemotherapeutic agents, often using dormancy as a shield. Their unique properties, including drug resistance and metastatic potential, pose challenges for effective targeting. These cells exploit certain metabolic processes for their maintenance and survival. One of these processes is autophagy, which generally helps in energy homeostasis but when hijacked by CSCs can help maintain their stemness. Thus, it is often referred as an Achilles heel in CSCs, as certain cancers tend to depend on autophagy for survival. Autophagy, while crucial for maintaining stemness in cancer stem cells (CSCs), can also serve as a vulnerability in certain contexts, making it a complex target for therapy. Regulators of autophagy like AMPK (5' adenosine monophosphate-activated protein kinase) also play a crucial role in maintaining CSCs stemness by helping CSCs in metabolic reprogramming in harsh environments. The purpose of this review is to elucidate the interplay between autophagy and AMPK in CSCs, highlighting the challenges in targeting autophagy and discussing therapeutic strategies to overcome these limitations. This review focuses on previous research on autophagy and its regulators in cancer biology, particularly in CSCs, addresses the remaining unanswered questions, and potential targets for therapy are also brought to attention.
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Affiliation(s)
- Lochana Kovale
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
| | - Manish Kumar Singh
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
| | - Joungmok Kim
- Department of Oral Biochemistry and Molecular Biology, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Joohun Ha
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
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12
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Khan MM, Yalamarty SSK, Rajmalani BA, Filipczak N, Torchilin VP. Recent strategies to overcome breast cancer resistance. Crit Rev Oncol Hematol 2024; 197:104351. [PMID: 38615873 DOI: 10.1016/j.critrevonc.2024.104351] [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: 01/23/2023] [Revised: 01/24/2024] [Accepted: 04/10/2024] [Indexed: 04/16/2024] Open
Abstract
Breast cancer is potentially a lethal disease and a leading cause of death in women. Chemotherapy and radiotherapy are the most frequently used treatment options. Drug resistance in advanced breast cancer limits the therapeutic output of treatment. The leading cause of resistance in breast cancer is endocrine and hormonal imbalance, particularly in triple negative and HER2 positive breast cancers. The efflux of drugs due to p-gp's activity is another leading cause of resistance. Breast cancer resistant protein also contributes significantly. Strategies used to combat resistance include the use of nanoparticles to target drug delivery by co-delivery of chemotherapeutic drugs and genes (siRNA and miRNA) that help to down-regulate genes causing resistance. The siRNA is specific and effectively silences p-gp and other proteins causing resistance. The use of chemosensitizers is also effective in overcoming resistance. Chemo-sensitizers sensitize cancer cells to the effects of chemotherapeutic drugs. Novel anti-neoplastic agents such as antibody-drug conjugates and mesenchymal stem cells are also effective tools used to improve the therapeutic response in breast cancer. Similarly, combination of photo/thermal ablation with chemotherapy can act to overcome breast cancer resistance. In this review, we focus on the mechanism of breast cancer resistance and the nanoparticle-based strategies used to combat resistance in breast cancer.
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Affiliation(s)
- Muhammad Muzamil Khan
- Center of Nanomedicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | | | - Bharat Ashok Rajmalani
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
| | - Nina Filipczak
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
| | - Vladimir P Torchilin
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA; Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA.
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13
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Azizidoost S, Nasrolahi A, Sheykhi-Sabzehpoush M, Anbiyaiee A, Khoshnam SE, Farzaneh M, Uddin S. Signaling pathways governing the behaviors of leukemia stem cells. Genes Dis 2024; 11:830-846. [PMID: 37692500 PMCID: PMC10491880 DOI: 10.1016/j.gendis.2023.01.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 01/02/2023] [Indexed: 08/28/2023] Open
Abstract
Leukemia is a malignancy in the blood that develops from the lymphatic system and bone marrow. Although various treatment options have been used for different types of leukemia, understanding the molecular pathways involved in the development and progression of leukemia is necessary. Recent studies showed that leukemia stem cells (LSCs) play essential roles in the pathogenesis of leukemia by targeting several signaling pathways, including Notch, Wnt, Hedgehog, and STAT3. LSCs are highly proliferative cells that stimulate tumor initiation, migration, EMT, and drug resistance. This review summarizes cellular pathways that stimulate and prevent LSCs' self-renewal, metastasis, and tumorigenesis.
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Affiliation(s)
- Shirin Azizidoost
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6193673111, Iran
| | - Ava Nasrolahi
- Infectious Ophthalmologic Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6193673111, Iran
| | - Mohadeseh Sheykhi-Sabzehpoush
- Department of Laboratory, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran 2193672411, Iran
| | - Amir Anbiyaiee
- Department of Surgery, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6193673111, Iran
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6193673111, Iran
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6193673111, Iran
| | - Shahab Uddin
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
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14
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Druzhkova I, Komarova A, Nikonova E, Baigildin V, Mozherov A, Shakirova Y, Lisitsa U, Shcheslavskiy V, Ignatova N, Shirshin E, Shirmanova M, Tunik S. Monitoring the Intracellular pH and Metabolic State of Cancer Cells in Response to Chemotherapy Using a Combination of Phosphorescence Lifetime Imaging Microscopy and Fluorescence Lifetime Imaging Microscopy. Int J Mol Sci 2023; 25:49. [PMID: 38203221 PMCID: PMC10779161 DOI: 10.3390/ijms25010049] [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: 10/25/2023] [Revised: 12/09/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
The extracellular matrix (ECM), in which collagen is the most abundant protein, impacts many aspects of tumor physiology, including cellular metabolism and intracellular pH (pHi), as well as the efficacy of chemotherapy. Meanwhile, the role of collagen in differential cell responses to treatment within heterogeneous tumor environments remains poorly investigated. In the present study, we simultaneously monitored the changes in pHi and metabolism in living colorectal cancer cells in vitro upon treatment with a chemotherapeutic combination, FOLFOX (5-fluorouracil, oxaliplatin and leucovorin). The pHi was followed using the new pH-sensitive probe BC-Ga-Ir, working in the mode of phosphorescence lifetime imaging (PLIM), and metabolism was assessed from the autofluorescence of the metabolic cofactor NAD(P)H using fluorescence lifetime imaging (FLIM) with a two-photon laser scanning microscope. To model the ECM, 3D collagen-based hydrogels were used, and comparisons with conventional monolayer cells were made. It was found that FOLFOX treatment caused an early temporal intracellular acidification (reduction in pHi), followed by a shift to more alkaline values, and changed cellular metabolism to a more oxidative state. The presence of unstructured collagen markedly reduced the cytotoxic effects of FOLFOX, and delayed and diminished the pHi and metabolic responses. These results support the observation that collagen is a factor in the heterogeneous response of cancer cells to chemotherapy and a powerful regulator of their metabolic behavior.
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Affiliation(s)
- Irina Druzhkova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 603005 Nizhny Novgorod, Russia; (A.K.); (A.M.); (U.L.); (V.S.); (N.I.); (M.S.)
| | - Anastasiya Komarova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 603005 Nizhny Novgorod, Russia; (A.K.); (A.M.); (U.L.); (V.S.); (N.I.); (M.S.)
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 603950 Nizhny Novgorod, Russia
| | - Elena Nikonova
- Laboratory of Clinical Biophotonics, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (E.N.); (E.S.)
| | - Vadim Baigildin
- Institute of Chemistry, Saint-Petersburg State University, 198504 St. Petersburg, Russia; (V.B.); (Y.S.)
| | - Artem Mozherov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 603005 Nizhny Novgorod, Russia; (A.K.); (A.M.); (U.L.); (V.S.); (N.I.); (M.S.)
| | - Yuliya Shakirova
- Institute of Chemistry, Saint-Petersburg State University, 198504 St. Petersburg, Russia; (V.B.); (Y.S.)
| | - Uliana Lisitsa
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 603005 Nizhny Novgorod, Russia; (A.K.); (A.M.); (U.L.); (V.S.); (N.I.); (M.S.)
| | - Vladislav Shcheslavskiy
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 603005 Nizhny Novgorod, Russia; (A.K.); (A.M.); (U.L.); (V.S.); (N.I.); (M.S.)
| | - Nadezhda Ignatova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 603005 Nizhny Novgorod, Russia; (A.K.); (A.M.); (U.L.); (V.S.); (N.I.); (M.S.)
| | - Evgeny Shirshin
- Laboratory of Clinical Biophotonics, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (E.N.); (E.S.)
- Faculty of Physics, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Marina Shirmanova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 603005 Nizhny Novgorod, Russia; (A.K.); (A.M.); (U.L.); (V.S.); (N.I.); (M.S.)
| | - Sergey Tunik
- Institute of Chemistry, Saint-Petersburg State University, 198504 St. Petersburg, Russia; (V.B.); (Y.S.)
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15
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Mariotto E, Rampazzo E, Bortolozzi R, Rruga F, Zeni I, Manfreda L, Marchioro C, Canton M, Cani A, Magni R, Luchini A, Bresolin S, Viola G, Persano L. Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma. Acta Neuropathol Commun 2023; 11:183. [PMID: 37978570 PMCID: PMC10655385 DOI: 10.1186/s40478-023-01679-7] [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: 08/03/2023] [Accepted: 10/26/2023] [Indexed: 11/19/2023] Open
Abstract
Chemotherapy resistance is considered one of the main causes of tumor relapse, still challenging researchers for the identification of the molecular mechanisms sustaining its emergence. Here, we setup and characterized chemotherapy-resistant models of Medulloblastoma (MB), one of the most lethal pediatric brain tumors, to uncover targetable vulnerabilities associated to their resistant phenotype. Integration of proteomic, transcriptomic and kinomic data revealed a significant deregulation of several pathways in resistant MB cells, converging to cell metabolism, RNA/protein homeostasis, and immune response, eventually impacting on patient outcome. Moreover, resistant MB cell response to a large library of compounds through a high-throughput screening (HTS), highlighted nucleoside metabolism as a relevant vulnerability of chemotolerant cells, with peculiar antimetabolites demonstrating increased efficacy against them and even synergism with conventional chemotherapeutics. Our results suggest that drug-resistant cells significantly rewire multiple cellular processes, allowing their adaptation to a chemotoxic environment, nevertheless exposing alternative actionable susceptibilities for their specific targeting.
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Affiliation(s)
- Elena Mariotto
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
- Unit of Biostatistics, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Via Loredan 18, 35131, Padua, Italy
| | - Elena Rampazzo
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy.
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy.
| | - Roberta Bortolozzi
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy.
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy.
- Section of Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo Meneghetti 2, 35131, Padua, Italy.
| | - Fatlum Rruga
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Ilaria Zeni
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
| | - Lorenzo Manfreda
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Chiara Marchioro
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Martina Canton
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Alice Cani
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Ruben Magni
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, MSN 1A9, Manassas, VA, 20110, USA
| | - Alessandra Luchini
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, MSN 1A9, Manassas, VA, 20110, USA
| | - Silvia Bresolin
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Giampietro Viola
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Luca Persano
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
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16
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Nisco A, Carvalho TMA, Tolomeo M, Di Molfetta D, Leone P, Galluccio M, Medina M, Indiveri C, Reshkin SJ, Cardone RA, Barile M. Increased demand for FAD synthesis in differentiated and stem pancreatic cancer cells is accomplished by modulating FLAD1 gene expression: the inhibitory effect of Chicago Sky Blue. FEBS J 2023; 290:4679-4694. [PMID: 37254652 DOI: 10.1111/febs.16881] [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: 01/13/2023] [Revised: 03/31/2023] [Accepted: 05/30/2023] [Indexed: 06/01/2023]
Abstract
FLAD1, along with its FAD synthase (FADS, EC 2.7.7.2) product, is crucial for flavin homeostasis and, due to its role in the mitochondrial respiratory chain and nuclear epigenetics, is closely related to cellular metabolism. Therefore, it is not surprising that it could be correlated with cancer. To our knowledge, no previous study has investigated FLAD1 prognostic significance in pancreatic ductal adenocarcinoma (PDAC). Thus, in the present work, the FAD synthesis process was evaluated in two PDAC cell lines: (a) PANC-1- and PANC-1-derived cancer stem cells (CSCs), presenting the R273H mutation in the oncosuppressor p53, and (b) MiaPaca2 and MiaPaca2-derived CSCs, presenting the R248W mutation in p53. As a control, HPDE cells expressing wt-p53 were used. FADS expression/activity increase was found with malignancy and even more with stemness. An increased FAD synthesis rate in cancer cell lines is presumably demanded by the increase in the FAD-dependent lysine demethylase 1 protein amount as well as by the increased expression levels of the flavoprotein subunit of complex II of the mitochondrial respiratory chain, namely succinate dehydrogenase. With the aim of proposing FADS as a novel target for cancer therapy, the inhibitory effect of Chicago Sky Blue on FADS enzymatic activity was tested on the recombinant 6His-hFADS2 (IC50 = 1.2 μm) and PANC-1-derived CSCs' lysate (IC50 = 2-10 μm). This molecule was found effective in inhibiting the growth of PANC-1 and even more of its derived CSC line, thus assessing its role as a potential chemotherapeutic drug.
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Affiliation(s)
- Alessia Nisco
- Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy
| | - Tiago M A Carvalho
- Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy
| | - Maria Tolomeo
- Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy
- Department of DiBEST (Biologia, Ecologia e Scienze della Terra), University of Calabria, Arcavacata di Rende, Italy
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy
| | - Piero Leone
- Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy
| | - Michele Galluccio
- Department of DiBEST (Biologia, Ecologia e Scienze della Terra), University of Calabria, Arcavacata di Rende, Italy
| | - Milagros Medina
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Instituto de Biocomputación y Física de Sistemas Complejos (BIFI) (GBsC-CSIC Joint Unit), University of Zaragoza, Spain
| | - Cesare Indiveri
- Department of DiBEST (Biologia, Ecologia e Scienze della Terra), University of Calabria, Arcavacata di Rende, Italy
- CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), Bari, Italy
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy
| | - Maria Barile
- Department of Biosciences, Biotechnologies, and Environment, University of Bari Aldo Moro, Italy
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17
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Erisik D, Ozdil B, Acikgoz E, Asker Abdikan CS, Yesin TK, Aktug H. Differences and Similarities between Colorectal Cancer Cells and Colorectal Cancer Stem Cells: Molecular Insights and Implications. ACS OMEGA 2023; 8:30145-30157. [PMID: 37636966 PMCID: PMC10448492 DOI: 10.1021/acsomega.3c02681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 07/26/2023] [Indexed: 08/29/2023]
Abstract
Malignant tumors are formed by diverse groups of cancer cells. Cancer stem cells (CSCs) are a subpopulation of heterogeneous cells identified in tumors that have the ability to self-renew and differentiate. Colorectal cancer (CRC), the third most frequent malignant tumor, is progressively being supported by evidence suggesting that CSCs are crucial in cancer development. We aim to identify molecular differences between CRC cells and CRC CSCs, as well as the effects of those differences on cell behavior in terms of migration, EMT, pluripotency, morphology, cell cycle/control, and epigenetic characteristics. The HT-29 cell line (human colorectal adenocarcinoma) and HT-29 CSCs (HT-29 CD133+/CD44+ cells) were cultured for 72 h. The levels of E-cadherin, KLF4, p53, p21, p16, cyclin D2, HDAC9, and P300 protein expression were determined using immunohistochemistry staining. The migration of cells was assessed by employing the scratch assay technique. Additionally, the scanning electron microscopy method was used to examine the morphological features of the cells, and their peripheral/central elemental ratios were compared with the help of EDS. Furthermore, a Muse cell cycle kit was utilized to determine the cell cycle analysis. The HT-29 CSC group exhibited high levels of expression for E-cadherin, p53, p21, p16, cyclin D2, HDAC9, and P300, whereas KLF4 was found to be high in the HT-29. The two groups did not exhibit any statistically significant differences in the percentages of cell cycle phases. The identification of specific CSC characteristics will allow for earlier cancer detection and the development of more effective precision oncology options.
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Affiliation(s)
- Derya Erisik
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
| | - Berrin Ozdil
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
- Department
of Histology and Embryology, Faculty of Medicine, Suleyman Demirel University, Isparta 32260, Turkey
| | - Eda Acikgoz
- Department
of Histology and Embryology, Faculty of Medicine, Yuzuncu Yil University, Van 65080, Turkey
| | | | - Taha Kadir Yesin
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
| | - Huseyin Aktug
- Department
of Histology and Embryology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
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18
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Du Y, Gupta P, Qin S, Sieber M. The role of metabolism in cellular quiescence. J Cell Sci 2023; 136:jcs260787. [PMID: 37589342 PMCID: PMC10445740 DOI: 10.1242/jcs.260787] [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: 08/18/2023] Open
Abstract
Cellular quiescence is a dormant, non-dividing cell state characterized by significant shifts in physiology and metabolism. Quiescence plays essential roles in a wide variety of biological processes, ranging from microbial sporulation to human reproduction and wound repair. Moreover, when the regulation of quiescence is disrupted, it can drive cancer growth and compromise tissue regeneration after injury. In this Review, we examine the dynamic changes in metabolism that drive and support dormant and transiently quiescent cells, including spores, oocytes and adult stem cells. We begin by defining quiescent cells and discussing their roles in key biological processes. We then examine metabolic factors that influence cellular quiescence in both healthy and disease contexts, and how these could be leveraged in the treatment of cancer.
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Affiliation(s)
- Yipeng Du
- UT Southwestern Medical Center, 5323 Harry Hines Blvd, MC9040 ND13.214, Dallas, TX 75390, USA
| | - Parul Gupta
- UT Southwestern Medical Center, 5323 Harry Hines Blvd, MC9040 ND13.214, Dallas, TX 75390, USA
| | - Shenlu Qin
- UT Southwestern Medical Center, 5323 Harry Hines Blvd, MC9040 ND13.214, Dallas, TX 75390, USA
| | - Matthew Sieber
- UT Southwestern Medical Center, 5323 Harry Hines Blvd, MC9040 ND13.214, Dallas, TX 75390, USA
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19
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Barguilla I, Maguer-Satta V, Guyot B, Pastor S, Marcos R, Hernández A. In Vitro Approaches to Determine the Potential Carcinogenic Risk of Environmental Pollutants. Int J Mol Sci 2023; 24:ijms24097851. [PMID: 37175558 PMCID: PMC10178670 DOI: 10.3390/ijms24097851] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/22/2023] [Accepted: 04/23/2023] [Indexed: 05/15/2023] Open
Abstract
One important environmental/health challenge is to determine, in a feasible way, the potential carcinogenic risk associated with environmental agents/exposures. Since a significant proportion of tumors have an environmental origin, detecting the potential carcinogenic risk of environmental agents is mandatory, as regulated by national and international agencies. The challenge mainly implies finding a way of how to overcome the inefficiencies of long-term trials with rodents when thousands of agents/exposures need to be tested. To such an end, the use of in vitro cell transformation assays (CTAs) was proposed, but the existing prevalidated CTAs do not cover the complexity associated with carcinogenesis processes and present serious limitations. To overcome such limitations, we propose to use a battery of assays covering most of the hallmarks of the carcinogenesis process. For the first time, we grouped such assays as early, intermediate, or advanced biomarkers which allow for the identification of the cells in the initiation, promotion or aggressive stages of tumorigenesis. Our proposal, as a novelty, points out that using a battery containing assays from all three groups can identify if a certain agent/exposure can pose a carcinogenic risk; furthermore, it can gather mechanistic insights into the mode of the action of a specific carcinogen. This structured battery could be very useful for any type of in vitro study, containing human cell lines aiming to detect the potential carcinogenic risks of environmental agents/exposures. In fact, here, we include examples in which these approaches were successfully applied. Finally, we provide a series of advantages that, we believe, contribute to the suitability of our proposed approach for the evaluation of exposure-induced carcinogenic effects and for the development of an alternative strategy for conducting an exposure risk assessment.
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Affiliation(s)
- Irene Barguilla
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France
| | | | - Boris Guyot
- CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France
| | - Susana Pastor
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
| | - Ricard Marcos
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
| | - Alba Hernández
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
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20
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Inflammation-Related Signature Profile Expression as a Poor Prognosis Marker after Oxaliplatin Treatment in Colorectal Cancer. Int J Mol Sci 2023; 24:ijms24043821. [PMID: 36835258 PMCID: PMC9965239 DOI: 10.3390/ijms24043821] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/30/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
Oxaliplatin is successfully used to eradicate micro-metastasis and improve survival, whereas the benefit of adjuvant chemotherapy in the early stages of colorectal cancer remains controversial. Inflammation plays a crucial role in colorectal cancer tumorigenesis. Inflammatory mechanisms are mediated by different immune cells through different cytokines, chemokines, and other proinflammatory molecules that trigger cell progression, an increase of cancer stem cell population, hyperplasia, and metastasis. This study focuses on the analysis of the oxaliplatin effect on tumourspheres formation efficiency, cell viability, cancer stem cells and stemness marker mRNA expression, as well as inflammation-related signature profile expression and its prognosis in primary- and metastatic-derived colorectal tumourspheres derived from colorectal cell lines isolated from the same patient 1 year apart. The results indicate that primary-derived colorectal tumourspheres respond to oxaliplatin, adapting to the adverse conditions through the modulation of CSCs and the stemness properties of tumourspheres. However, metastatic-derived colorectal tumourspheres response led to the release of cytokines and chemokines, promoting an inflammatory process. In addition, the expression of inflammatory markers showing greater difference between primary and metastatic tumours after oxaliplatin treatment correlates with poor prognosis in KM survival studies and is associated with a metastatic phenotype. Our data demonstrated that oxaliplatin triggers an inflammation-related signature profile expression in primary-derived colorectal tumourspheres, related with poor prognosis and a metastatic phenotype, which allow the tumour cells to adapt to the adverse condition. These data highlight the need for of drug testing and personalized medicine in the early stages of colorectal cancer.
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21
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Kufe D. Dependence on MUC1-C in Progression of Neuroendocrine Prostate Cancer. Int J Mol Sci 2023; 24:3719. [PMID: 36835130 PMCID: PMC9967814 DOI: 10.3390/ijms24043719] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/11/2023] [Accepted: 02/11/2023] [Indexed: 02/16/2023] Open
Abstract
Castration resistant prostate cancer (CRPC) is responsive to androgen receptor (AR) axis targeted agents; however, patients invariably relapse with resistant disease that often progresses to neuroendocrine prostate cancer (NEPC). Treatment-related NEPC (t-NEPC) is highly aggressive with limited therapeutic options and poor survival outcomes. The molecular basis for NEPC progression remains incompletely understood. The MUC1 gene evolved in mammals to protect barrier tissues from loss of homeostasis. MUC1 encodes the transmembrane MUC1-C subunit, which is activated by inflammation and contributes to wound repair. However, chronic activation of MUC1-C contributes to lineage plasticity and carcinogenesis. Studies in human NEPC cell models have demonstrated that MUC1-C suppresses the AR axis and induces the Yamanaka OSKM pluripotency factors. MUC1-C interacts directly with MYC and activates the expression of the BRN2 neural transcription factor (TF) and other effectors, such as ASCL1, of the NE phenotype. MUC1-C also induces the NOTCH1 stemness TF in promoting the NEPC cancer stem cell (CSC) state. These MUC1-C-driven pathways are coupled with activation of the SWI/SNF embryonic stem BAF (esBAF) and polybromo-BAF (PBAF) chromatin remodeling complexes and global changes in chromatin architecture. The effects of MUC1-C on chromatin accessibility integrate the CSC state with the control of redox balance and induction of self-renewal capacity. Importantly, targeting MUC1-C inhibits NEPC self-renewal, tumorigenicity and therapeutic resistance. This dependence on MUC1-C extends to other NE carcinomas, such as SCLC and MCC, and identify MUC1-C as a target for the treatment of these aggressive malignancies with the anti-MUC1 agents now under clinical and preclinical development.
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Affiliation(s)
- Donald Kufe
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
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22
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Kahn M. A Metabolic Smorgasbord Drives and Sustains CSC Heterogeneity. Cancers (Basel) 2023; 15:343. [PMID: 36672293 PMCID: PMC9856803 DOI: 10.3390/cancers15020343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 01/02/2023] [Indexed: 01/07/2023] Open
Abstract
A deeper understanding of the biology of therapy resistance is important for the development of optimal strategies to attain complete cancer cures [...].
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Affiliation(s)
- Michael Kahn
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
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23
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Gwynne WD, Suk Y, Custers S, Mikolajewicz N, Chan JK, Zador Z, Chafe SC, Zhai K, Escudero L, Zhang C, Zaslaver O, Chokshi C, Shaikh MV, Bakhshinyan D, Burns I, Chaudhry I, Nachmani O, Mobilio D, Maich WT, Mero P, Brown KR, Quaile AT, Venugopal C, Moffat J, Montenegro-Burke JR, Singh SK. Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma. Cancer Cell 2022; 40:1488-1502.e7. [PMID: 36368321 DOI: 10.1016/j.ccell.2022.10.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 09/09/2022] [Accepted: 10/06/2022] [Indexed: 11/12/2022]
Abstract
MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here, we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on target, leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell-cycle arrest and apoptosis. We further show that an orally available small-molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.
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Affiliation(s)
- William D Gwynne
- Department of Surgery, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Yujin Suk
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Michael G DeGroote School of Medicine, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Stefan Custers
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Nicholas Mikolajewicz
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College St, Toronto, ON M5S 3E1, Canada
| | - Jeremy K Chan
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College St, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Zsolt Zador
- Department of Surgery, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Shawn C Chafe
- Department of Surgery, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Kui Zhai
- Department of Surgery, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Laura Escudero
- Department of Surgery, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Cunjie Zhang
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College St, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Olga Zaslaver
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College St, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Chirayu Chokshi
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Muhammad Vaseem Shaikh
- Department of Surgery, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - David Bakhshinyan
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Ian Burns
- Michael G DeGroote School of Medicine, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Iqra Chaudhry
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Omri Nachmani
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College St, Toronto, ON M5S 3E1, Canada
| | - Daniel Mobilio
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - William T Maich
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Patricia Mero
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College St, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Kevin R Brown
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College St, Toronto, ON M5S 3E1, Canada
| | - Andrew T Quaile
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College St, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Chitra Venugopal
- Department of Surgery, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Jason Moffat
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College St, Toronto, ON M5S 3E1, Canada; Institute for Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - J Rafael Montenegro-Burke
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College St, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
| | - Sheila K Singh
- Department of Surgery, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada; Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
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24
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PRUSTY DEBASISH, Manna SK. Metabolic Reprogramming in Cancer. DRUG METABOLISM HANDBOOK 2022:841-892. [DOI: 10.1002/9781119851042.ch25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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25
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Papadaki S, Magklara A. Regulation of Metabolic Plasticity in Cancer Stem Cells and Implications in Cancer Therapy. Cancers (Basel) 2022; 14:5912. [PMID: 36497394 PMCID: PMC9741285 DOI: 10.3390/cancers14235912] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/23/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022] Open
Abstract
Cancer stem cells (CSCs), a subpopulation of tumor cells with self-renewal capacity, have been associated with tumor initiation, progression, and therapy resistance. While the bulk of tumor cells mainly use glycolysis for energy production, CSCs have gained attention for their ability to switch between glycolysis and oxidative phosphorylation, depending on their energy needs and stimuli from their microenvironment. This metabolic plasticity is mediated by signaling pathways that are also implicated in the regulation of CSC properties, such as the Wnt/β-catenin, Notch, and Hippo networks. Two other stemness-associated processes, autophagy and hypoxia, seem to play a role in the metabolic switching of CSCs as well. Importantly, accumulating evidence has linked the metabolic plasticity of CSCs to their increased resistance to treatment. In this review, we summarize the metabolic signatures of CSCs and the pathways that regulate them; we especially highlight research data that demonstrate the metabolic adaptability of these cells and their role in stemness and therapy resistance. As the development of drug resistance is a major challenge for successful cancer treatment, the potential of specific elimination of CSCs through targeting their metabolism is of great interest and it is particularly examined.
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Affiliation(s)
- Styliani Papadaki
- Department of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece
| | - Angeliki Magklara
- Department of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece
- Biomedical Research Institute–Foundation for Research and Technology, 45110 Ioannina, Greece
- Institute of Biosciences, University Research Center of Ioannina (URCI), 45110 Ioannina, Greece
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26
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Aramini B, Masciale V, Grisendi G, Bertolini F, Maur M, Guaitoli G, Chrystel I, Morandi U, Stella F, Dominici M, Haider KH. Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence. Cancers (Basel) 2022; 14:cancers14040976. [PMID: 35205721 PMCID: PMC8869911 DOI: 10.3390/cancers14040976] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 02/12/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Cancer is one of the most debated problems all over the world. Cancer stem cells are considered responsible of tumor initiation, metastasis, drug resistance, and recurrence. This subpopulation of cells has been found into the tumor bulk and showed the capacity to self-renew, differentiate, up to generate a new tumor. In the last decades, several studies have been set on the molecular mechanisms behind their specific characteristics as the Wnt/β-catenin signaling, Notch signaling, Hedgehog signaling, transcription factors, etc. The most powerful part of CSCs is represented by the niches as “promoter” of their self-renewal and “protector” from the common oncological treatment as chemotherapy and radiotherapy. In our review article we highlighted the primary mechanisms involved in CSC tumorigenesis for the setting of further targets to control the metastatic process. Abstract Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process.
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Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Experimental Diagnostic and Specialty Medicine–DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy;
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
- Correspondence:
| | - Valentina Masciale
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Federica Bertolini
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Michela Maur
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Giorgia Guaitoli
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Isca Chrystel
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Uliano Morandi
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
| | - Franco Stella
- Division of Thoracic Surgery, Department of Experimental Diagnostic and Specialty Medicine–DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy;
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
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27
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Korsching E, Matschke J, Hotfilder M. Splice variants denote differences between a cancer stem cell side population of EWSR1‑ERG‑based Ewing sarcoma cells, its main population and EWSR1‑FLI‑based cells. Int J Mol Med 2022; 49:39. [PMID: 35088879 PMCID: PMC8815407 DOI: 10.3892/ijmm.2022.5094] [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: 11/12/2021] [Accepted: 12/17/2021] [Indexed: 11/06/2022] Open
Abstract
Ewing sarcoma is a challenging cancer entity, which, besides the characteristic presence of a fusion gene, is driven by multiple alternative splicing events. So far, splice variants in Ewing sarcoma cells were mainly analyzed for EWSR1‑FLI1. The present study provided a comprehensive alternative splicing study on CADO‑ES1, an Ewing model cell line for an EWSR1‑ERG fusion gene. Based on a well‑-characterized RNA‑sequencing dataset with extensive control mechanisms across all levels of analysis, the differential spliced genes in Ewing cancer stem cells were ATP13A3 and EPB41, while the main population was defined by ACADVL, NOP58 and TSPAN3. All alternatively spliced genes were further characterized by their Gene Ontology (GO) terms and by their membership in known protein complexes. These results confirm and extend previous studies towards a systematic whole‑transcriptome analysis. A highlight is the striking segregation of GO terms associated with five basic splice events. This mechanistic insight, together with a coherent integration of all observations with prior knowledge, indicates that EWSR1‑ERG is truly a close twin to EWSR1‑FLI1, but still exhibits certain individuality. Thus, the present study provided a measure of variability in Ewing sarcoma, whose understanding is essential both for clinical procedures and basic mechanistic insight.
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Affiliation(s)
- Eberhard Korsching
- Institute of Bioinformatics, Faculty of Medicine, University of Münster, D‑48149 Münster, Germany
| | - Julian Matschke
- Institute of Bioinformatics, Faculty of Medicine, University of Münster, D‑48149 Münster, Germany
| | - Marc Hotfilder
- Department of Pediatric Hematology and Oncology, University Hospital Münster, D‑48149 Münster, Germany
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28
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Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies. Int J Mol Sci 2021; 22:ijms222111669. [PMID: 34769099 PMCID: PMC8584029 DOI: 10.3390/ijms222111669] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/23/2021] [Accepted: 10/23/2021] [Indexed: 02/07/2023] Open
Abstract
As a multifactorial disease, treatment of cancer depends on understanding unique mechanisms involved in its progression. The cancer stem cells (CSCs) are responsible for tumor stemness and by enhancing colony formation, proliferation as well as metastasis, and these cells can also mediate resistance to therapy. Furthermore, the presence of CSCs leads to cancer recurrence and therefore their complete eradication can have immense therapeutic benefits. The present review focuses on targeting CSCs by natural products in cancer therapy. The growth and colony formation capacities of CSCs have been reported can be attenuated by the dietary agents. These compounds can induce apoptosis in CSCs and reduce tumor migration and invasion via EMT inhibition. A variety of molecular pathways including STAT3, Wnt/β-catenin, Sonic Hedgehog, Gli1 and NF-κB undergo down-regulation by dietary agents in suppressing CSC features. Upon exposure to natural agents, a significant decrease occurs in levels of CSC markers including CD44, CD133, ALDH1, Oct4 and Nanog to impair cancer stemness. Furthermore, CSC suppression by dietary agents can enhance sensitivity of tumors to chemotherapy and radiotherapy. In addition to in vitro studies, as well as experiments on the different preclinical models have shown capacity of natural products in suppressing cancer stemness. Furthermore, use of nanostructures for improving therapeutic impact of dietary agents is recommended to rapidly translate preclinical findings for clinical use.
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29
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Huang B, Yan X, Li Y. Cancer Stem Cell for Tumor Therapy. Cancers (Basel) 2021; 13:cancers13194814. [PMID: 34638298 PMCID: PMC8508418 DOI: 10.3390/cancers13194814] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/13/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Although many methods have been applied in clinical treatment for tumors, they still always show a poor prognosis. Molecule targeted therapy has revolutionized tumor therapy, and a proper target must be found urgently. With a crucial role in tumor development, metastasis and recurrence, cancer stem cells have been found to be a feasible and potential target for tumor therapy. We list the unique biological characteristics of cancer stem cells and summarize the recent strategies to target cancer stem cells for tumor therapy, through which we hope to provide a comprehensive understanding of cancer stem cells and find a better combinational strategy to target cancer stem cells for tumor therapy. Abstract Tumors pose a significant threat to human health. Although many methods, such as operations, chemotherapy and radiotherapy, have been proposed to eliminate tumor cells, the results are unsatisfactory. Targeting therapy has shown potential due to its specificity and efficiency. Meanwhile, it has been revealed that cancer stem cells (CSCs) play a crucial role in the genesis, development, metastasis and recurrence of tumors. Thus, it is feasible to inhibit tumors and improve prognosis via targeting CSCs. In this review, we provide a comprehensive understanding of the biological characteristics of CSCs, including mitotic pattern, metabolic phenotype, therapeutic resistance and related mechanisms. Finally, we summarize CSCs targeted strategies, including targeting CSCs surface markers, targeting CSCs related signal pathways, targeting CSC niches, targeting CSC metabolic pathways, inducing differentiation therapy and immunotherapy (tumor vaccine, CAR-T, oncolytic virus, targeting CSCs–immune cell crosstalk and immunity checkpoint inhibitor). We highlight the potential of immunity therapy and its combinational anti-CSC therapies, which are composed of different drugs working in different mechanisms.
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Affiliation(s)
- Binjie Huang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
| | - Xin Yan
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
- Correspondence: ; Tel.: +86-138-9361-5421
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30
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He S, Tian S, He X, Le X, Ning Y, Chen J, Chen H, Mu J, Xu K, Xiang Q, Wu Y, Chen J, Xiang T. Multiple targeted self-emulsifying compound RGO reveals obvious anti-tumor potential in hepatocellular carcinoma. Mol Ther Oncolytics 2021; 22:604-616. [PMID: 34589579 PMCID: PMC8449031 DOI: 10.1016/j.omto.2021.08.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 08/12/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly vascularized, inflammatory, and abnormally proliferating tumor. Monotherapy is often unable to effectively and comprehensively inhibit the progress of HCC. In present study, we selected ginsenoside Rg3, ganoderma lucidum polysaccharide (GLP), and oridonin as the combined therapy. These three plant monomers play important roles in anti-angiogenesis, immunological activation, and apoptosis promotion, respectively. However, the low solubility and poor bioavailability seriously hinder their clinical application. To resolve these problems, we constructed a new drug, Rg3, GLP, and oridonin self-microemulsifying drug delivery system (RGO-SMEDDS). We found that this drug effectively inhibits the progression of HCC by simultaneously targeting multiple signaling pathways. RGO-SMEDDS restored immune function by suppressing the production of immunosuppressive cytokine and M2-polarized macrophages, reduced angiogenesis by downregulation of vascular endothelial growth factor and its receptor, and retarded proliferation by inhibiting the epidermal growth factor receptor EGFR/AKT/epidermal growth factor receptor/protein kinase B/glycogen synthase kinase-3 (GSK3) signaling pathway. In addition, RGO-SMEDDS showed considerable safety in acute toxicity tests. Results from this study show that RGO-SMEDDS is a promising therapy for the treatment of HCC.
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Affiliation(s)
- Sanxiu He
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shaorong Tian
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoqian He
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xin Le
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yijiao Ning
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jialin Chen
- Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Hongyi Chen
- Chongqing College of Humanities, Science & Technology, Chongqing, China
| | - Junhao Mu
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ke Xu
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qin Xiang
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yue Wu
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiong Chen
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Tingxiu Xiang
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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The metabolic flexibility of quiescent CSC: implications for chemotherapy resistance. Cell Death Dis 2021; 12:835. [PMID: 34482364 PMCID: PMC8418609 DOI: 10.1038/s41419-021-04116-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 08/10/2021] [Accepted: 08/20/2021] [Indexed: 12/11/2022]
Abstract
Quiescence has been observed in stem cells (SCs), including adult SCs and cancer SCs (CSCs). Conventional chemotherapies mostly target proliferating cancer cells, while the quiescent state favors CSCs escape to chemotherapeutic drugs, leaving risks for tumor recurrence or metastasis. The tumor microenvironment (TME) provides various signals that maintain resident quiescent CSCs, protect them from immune surveillance, and facilitates their recurrence potential. Since the TME has the potential to support and initiate stem cell-like programs in cancer cells, targeting the TME components may prove to be a powerful modality for the treatment of chemotherapy resistance. In addition, an increasing number of studies have discovered that CSCs exhibit the potential of metabolic flexibility when metabolic substrates are limited, and display increased robustness in response to stress. Accompanied by chemotherapy that targets proliferative cancer cells, treatments that modulate CSC quiescence through the regulation of metabolic pathways also show promise. In this review, we focus on the roles of metabolic flexibility and the TME on CSCs quiescence and further discuss potential treatments of targeting CSCs and the TME to limit chemotherapy resistance.
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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Hagiwara M, Fushimi A, Yamashita N, Bhattacharya A, Rajabi H, Long MD, Yasumizu Y, Oya M, Liu S, Kufe D. MUC1-C activates the PBAF chromatin remodeling complex in integrating redox balance with progression of human prostate cancer stem cells. Oncogene 2021; 40:4930-4940. [PMID: 34163028 PMCID: PMC8321896 DOI: 10.1038/s41388-021-01899-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 05/20/2021] [Accepted: 06/07/2021] [Indexed: 12/19/2022]
Abstract
The polybromo-associated PBAF (SWI/SNF) chromatin remodeling complex, which includes PBRM1, ARID2, and BRD7, regulates cell differentiation and genomic integrity. MUC1-C is an oncogenic protein that drives lineage plasticity in prostate cancer (PC) progression. The present work demonstrates that MUC1-C induces PBRM1, ARID2, and BRD7 expression by the previously unrecognized E2F1-mediated activation of their respective promoters. The functional significance of the MUC1-C→PBAF pathway is supported by demonstrating involvement of MUC1-C in associating with nuclear PBAF and driving the NRF2 antioxidant gene transcriptome in PC cells. Mechanistically, MUC1-C forms a complex with NRF2 and PBRM1 on the NRF2 target SLC7A11 gene that encodes the xCT cystine-glutamate antiporter, increases chromatin accessibility and induces SLC7A11/xCT expression. We also show that MUC1-C and PBRM1 are necessary for induction of other NRF2 target genes, including G6PD and PGD that regulate the pentose phosphate pathway. Our results further demonstrate that MUC1-C integrates activation of PBRM1 with the regulation of antioxidant genes, ROS levels, pluripotency factor expression and the cancer stem cell (CSC) state. These findings reveal a role for MUC1-C in regulating PBAF, redox balance and lineage plasticity of PC CSC progression. Our findings also uncover involvement of MUC1-C in integrating the PBAF and BAF pathways in cancer.
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Affiliation(s)
- Masayuki Hagiwara
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Atsushi Fushimi
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Nami Yamashita
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - Hasan Rajabi
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Mark D Long
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Yota Yasumizu
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Mototsugu Oya
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Donald Kufe
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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Wang JM, Gao Q, Zhang Q, Hao L, Jiang JY, Huyan LY, Liu BQ, Yan J, Li C, Wang HQ. Implication of BAG5 downregulation in metabolic reprogramming of cisplatin-resistant ovarian cancer cells via mTORC2 signaling pathway. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1868:119076. [PMID: 34126157 DOI: 10.1016/j.bbamcr.2021.119076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/31/2021] [Accepted: 06/03/2021] [Indexed: 12/11/2022]
Abstract
Ovarian cancer is the most frequent cause of gynecologic malignancies associated death. Primary or acquired cisplatin resistance is frequently occurred during ovarian cancer therapy. Cancer stem cells (CSC) tend to form minimal residual disease after chemotherapy and are implicated in relapse. The ability of cancer cells to reprogram their metabolism has recently been related with maintenance of CSC and resistance to chemotherapies. The current study found that BAG5 expression was decreased in cisplatin-resistant ovarian cancer cells and clinical tissues. Our data demonstrated that BAG5 knockdown was implicated in metabolic reprogramming and maintenance of cancer stem cell (CSC)-like features of ovarian cancer cells via regulation of Rictor and subsequent mTORC2 signaling pathway. In addition, the current study demonstrated that Bcl6 upregulation was responsible for repression of BAG5 transactivation via recruitment on the BAG5 promoter in cisplatin-resistant ovarian cancer. The current study also demonstrated reverse correlations between BAG5 and Bcl6, BAG5 and Rictor in ovarian serous adenocarcinoma tissues. Collectively, the current study identified the implication of Bcl6/BAG5/Rictor-mTORC2 signaling pathway in metabolic reprograming and maintenance of CSC-like features in cisplatin-resistant ovarian cancer cells. Therefore, further studies on the mechanism underlying regulation of metabolic reprogramming and CSC-like characteristics of cisplatin-resistant ovarian cancer cells may contribute to the establishment of novel therapeutic strategy for cisplatin-resistance.
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Affiliation(s)
- Jia-Mei Wang
- Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110026, China; Department of Laboratory Medicine, the 1st affiliated hospital, China Medical University, Shenyang 110001, China
| | - Qi Gao
- Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110026, China
| | - Qi Zhang
- Criminal Investigation Police University of China, Shenyang 110854, China
| | - Liang Hao
- Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110026, China
| | - Jing-Yi Jiang
- Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110026, China
| | - Ling-Yue Huyan
- 5+3 integrated clinical medicine 103K, China Medical University, Shenyang 110026, China
| | - Bao-Qin Liu
- Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110026, China
| | - Jing Yan
- Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110026, China
| | - Chao Li
- Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110026, China
| | - Hua-Qin Wang
- Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110026, China.
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35
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Ni H, Qin H, Sun C, Liu Y, Ruan G, Guo Q, Xi T, Xing Y, Zheng L. MiR-375 reduces the stemness of gastric cancer cells through triggering ferroptosis. Stem Cell Res Ther 2021; 12:325. [PMID: 34090492 PMCID: PMC8180146 DOI: 10.1186/s13287-021-02394-7] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/17/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Gastric cancer stem cells (CSCs) are the main causes of metastasis and drug resistance. We previously indicated that miR-375 can inhibit Helicobacter pylori-induced gastric carcinogenesis; here, we aim to explore the effects and mechanisms of miR-375 on gastric cancer (GC) cell stemness. METHODS Lentivirus infection was used to construct GC cells with ectopic expression of miR-375. In vitro and in vivo experiments, including analysis of tumor spheroid formation, CD44+ sub-population with stemness, stemness marker expression, and tumor-initiating ability, were performed to evaluate the effects of miR-375 on the stemness of GC cells. Furthermore, microarray and bioinformatics analysis were performed to search the potential targets of miR-375 in GC cells. Luciferase reporter, RNA immunoprecipitation, and RNA-FISH assays were carried out to verify the targeting of miR-375. Subsequently, combined with tissue microarray analysis, erastin-resistant GC cells, transmission electron microscopy, a series of agonists and oxidative stress markers, the underlying mechanisms contributing to miR-375-mediated effects were explored. RESULTS MiR-375 reduced the stemness of GC cells in vitro and in vivo. Mechanistically, SLC7A11 was identified as a direct target of miR-375 and miR-375 attenuated the stemness of GC cells mainly through triggering SLC7A11-dependent ferroptosis. CONCLUSION MiR-375 can trigger the ferroptosis through targeting SLC7A11, which is essential for miR-375-mediated inhibition on GC cell stemness. These results suggest that the miR-375/SLC7A11 regulatory axis could serve as a potential target to provoke the ferroptosis and thus attenuate the stemness of GC cells.
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Affiliation(s)
- Haiwei Ni
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Hai Qin
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Cheng Sun
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Yichen Liu
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Guojing Ruan
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Qianqian Guo
- Department of Pharmacy, the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, People's Republic of China
| | - Tao Xi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
| | - Yingying Xing
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
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Cioce M, Fazio VM. EphA2 and EGFR: Friends in Life, Partners in Crime. Can EphA2 Be a Predictive Biomarker of Response to Anti-EGFR Agents? Cancers (Basel) 2021; 13:cancers13040700. [PMID: 33572284 PMCID: PMC7915460 DOI: 10.3390/cancers13040700] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/03/2021] [Accepted: 02/04/2021] [Indexed: 12/14/2022] Open
Abstract
The Eph receptors represent the largest group among Receptor Tyrosine kinase (RTK) families. The Eph/ephrin signaling axis plays center stage during development, and the deep perturbation of signaling consequent to its dysregulation in cancer reveals the multiplicity and complexity underlying its function. In the last decades, they have emerged as key players in solid tumors, including colorectal cancer (CRC); however, what causes EphA2 to switch between tumor-suppressive and tumor-promoting function is still an active theater of investigation. This review summarizes the recent advances in understanding EphA2 function in cancer, with detail on the molecular determinants of the oncogene-tumor suppressor switch function of EphA2. We describe tumor context-specific examples of EphA2 signaling and the emerging role EphA2 plays in supporting cancer-stem-cell-like populations and overcoming therapy-induced stress. In such a frame, we detail the interaction of the EphA2 and EGFR pathway in solid tumors, including colorectal cancer. We discuss the contribution of the EphA2 oncogenic signaling to the resistance to EGFR blocking agents, including cetuximab and TKIs.
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Affiliation(s)
- Mario Cioce
- Laboratory of Molecular Medicine and Biotechnology, Department of Medicine, University Campus Bio-Medico of Rome, 00128 Rome, Italy
- Correspondence: (M.C.); (V.M.F.)
| | - Vito Michele Fazio
- Laboratory of Molecular Medicine and Biotechnology, Department of Medicine, University Campus Bio-Medico of Rome, 00128 Rome, Italy
- Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
- Institute of Translational Pharmacology, National Research Council of Italy (CNR), 00133 Rome, Italy
- Correspondence: (M.C.); (V.M.F.)
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Kahya U, Köseer AS, Dubrovska A. Amino Acid Transporters on the Guard of Cell Genome and Epigenome. Cancers (Basel) 2021; 13:E125. [PMID: 33401748 PMCID: PMC7796306 DOI: 10.3390/cancers13010125] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/26/2020] [Accepted: 12/27/2020] [Indexed: 02/06/2023] Open
Abstract
Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to the damage of vital macromolecules, such as DNA, proteins, and lipids, causing genomic instability and further tumor evolution. One of the hallmarks of cancer metabolism is deregulated amino acid uptake. In fast-growing tumors, amino acids are not only the source of energy and building intermediates but also critical regulators of redox homeostasis. Amino acid uptake regulates the intracellular glutathione (GSH) levels, endoplasmic reticulum stress, unfolded protein response signaling, mTOR-mediated antioxidant defense, and epigenetic adaptations of tumor cells to oxidative stress. This review summarizes the role of amino acid transporters as the defender of tumor antioxidant system and genome integrity and discusses them as promising therapeutic targets and tumor imaging tools.
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Affiliation(s)
- Uğur Kahya
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
| | - Ayşe Sedef Köseer
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Anna Dubrovska
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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