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1
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El Yousfi Y, Fernández-Farrán FJ, Oliver FJ, López-Rivas A, Yerbes R. Regulation of ER stress-induced apoptotic and inflammatory responses via YAP/TAZ-mediated control of the TRAIL-R2/DR5 signaling pathway. Cell Death Discov 2025; 11:42. [PMID: 39904986 PMCID: PMC11794427 DOI: 10.1038/s41420-025-02335-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/10/2025] [Accepted: 01/28/2025] [Indexed: 02/06/2025] Open
Abstract
In tumors, cancer cells are frequently exposed to adverse environmental conditions that result in endoplasmic reticulum (ER) stress. Mechanical signals emerging from extracellular matrix (ECM) rigidity and cell shape regulate the activity of transcriptional co-activators Yes-associated protein (YAP) and its paralog Transcriptional Coactivator with PDZ-binding motif (TAZ). However, the role of ECM rigidity and YAP/TAZ in tumor cell fate decisions under ER stress remains relatively unexplored. Our results suggest that the YAP/TAZ system plays an important role in the control of ER stress-induced cell death by mechanical signaling arising from ECM stiffness in tumor cells. Mechanistically, YAP/TAZ regulates apoptosis induced by ER stress in tumor cells by controlling the activation of the TRAIL-R2/DR5-mediated extrinsic apoptotic pathway through a dual mechanism. On the one hand, the YAP/TAZ system prevents intracellular TRAIL-R2/DR5 clustering in tumor cells. On the other hand, it inhibits cFLIP down-regulation in tumor cells experiencing ER stress. In addition, YAP/TAZ controls the expression of pro-inflammatory interleukin-8 (IL-8/CXCL8) in tumor cells undergoing ER stress by a TRAIL-R2/DR5/caspase-8-dependent mechanism. Although other mechanisms may also be involved in controlling cell death and inflammation in tumor cells facing environmental stress, our results support a model in which regulation of the subcellular localization and activity of the YAP/TAZ transcriptional co-activators could contribute to the microenvironmental control of cell fate decisions in tumor cells undergoing ER stress.
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Affiliation(s)
- Y El Yousfi
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain
| | - F J Fernández-Farrán
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain
| | - F J Oliver
- Instituto de Parasitología y Biomedicina López Neyra, CSIC, Centro de Investigación Biomédica en Red de Cáncer CIBERONC, Granada, Spain
| | - A López-Rivas
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain
| | - R Yerbes
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Seville, Spain.
- Medical Physiology and Biophysics Department, Universidad de Sevilla and Instituto de Biomedicina de Sevilla (IBiS) (Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla), Seville, Spain.
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2
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Mackiewicz J, Tomczak J, Lisek M, Sakowicz A, Guo F, Boczek T. NFATc4 Knockout Promotes Neuroprotection and Retinal Ganglion Cell Regeneration After Optic Nerve Injury. Mol Neurobiol 2024; 61:9383-9401. [PMID: 38639863 PMCID: PMC11496353 DOI: 10.1007/s12035-024-04129-0] [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] [Accepted: 03/19/2024] [Indexed: 04/20/2024]
Abstract
Retinal ganglion cells (RGCs), neurons transmitting visual information via the optic nerve, fail to regenerate their axons after injury. The progressive loss of RGC function underlies the pathophysiology of glaucoma and other optic neuropathies, often leading to irreversible blindness. Therefore, there is an urgent need to identify the regulators of RGC survival and the regenerative program. In this study, we investigated the role of the family of transcription factors known as nuclear factor of activated T cells (NFAT), which are expressed in the retina; however, their role in RGC survival after injury is unknown. Using the optic nerve crush (ONC) model, widely employed to study optic neuropathies and central nervous system axon injury, we found that NFATc4 is specifically but transiently up-regulated in response to mechanical injury. In the injured retina, NFATc4 immunolocalized primarily to the ganglionic cell layer. Utilizing NFATc4-/- and NFATc3-/- mice, we demonstrated that NFATc4, but not NFATc3, knockout increased RGC survival, improved retina function, and delayed axonal degeneration. Microarray screening data, along with decreased immunostaining of cleaved caspase-3, revealed that NFATc4 knockout was protective against ONC-induced degeneration by suppressing pro-apoptotic signaling. Finally, we used lentiviral-mediated NFATc4 delivery to the retina of NFATc4-/- mice and reversed the pro-survival effect of NFATc4 knockout, conclusively linking the enhanced survival of injured RGCs to NFATc4-dependent mechanisms. In summary, this study is the first to demonstrate that NFATc4 knockout may confer transient RGC neuroprotection and decelerate axonal degeneration after injury, providing a potent therapeutic strategy for optic neuropathies.
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Affiliation(s)
- Joanna Mackiewicz
- Department of Molecular Neurochemistry, Medical University of Lodz, Lodz, Poland
| | - Julia Tomczak
- Department of Molecular Neurochemistry, Medical University of Lodz, Lodz, Poland
| | - Malwina Lisek
- Department of Molecular Neurochemistry, Medical University of Lodz, Lodz, Poland
| | - Agata Sakowicz
- Department of Medical Biotechnology, Medical University of Lodz, Lodz, Poland
| | - Feng Guo
- Department of Pharmaceutical Toxicology, China Medical University, Shenyang, China.
| | - Tomasz Boczek
- Department of Molecular Neurochemistry, Medical University of Lodz, Lodz, Poland.
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3
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Zhang L, Xia J. N6-Methyladenosine Methylation of mRNA in Cell Apoptosis. Mol Neurobiol 2024; 61:3934-3948. [PMID: 38040996 DOI: 10.1007/s12035-023-03813-x] [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: 11/24/2022] [Accepted: 11/16/2023] [Indexed: 12/03/2023]
Abstract
Apoptosis, a highly controlled homeostatic mechanism that eliminates single cells without destroying tissue function, occurs during growing development and senescence. N6-methyladenosine (m6A), as the most common internal modification of eukaryotic mRNA, fine-tunes gene expression by regulating many aspects of mRNA metabolism, such as splicing, nucleation, stability, translation, and degradation. Remarkably, recent reports have indicated that aberrant methylation of m6A-related RNA may directly or indirectly influence the expression of apoptosis-related genes, thus regulating the process of cell apoptosis. In this review, we summarized the relationship between m6A modification and cell apoptosis, especially its role in the nervous system, and analyzed the limitations of the current research.
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Affiliation(s)
- Lin Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Jian Xia
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
- Clinical Research Center for Cerebrovascular Disease of Hunan Province, Central South University, Changsha, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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4
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Choi J, Ceribelli M, Phelan JD, Häupl B, Huang DW, Wright GW, Hsiao T, Morris V, Ciccarese F, Wang B, Corcoran S, Scheich S, Yu X, Xu W, Yang Y, Zhao H, Zhou J, Zhang G, Muppidi J, Inghirami GG, Oellerich T, Wilson WH, Thomas CJ, Staudt LM. Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas. Cancer Cell 2024; 42:833-849.e12. [PMID: 38701792 PMCID: PMC11168741 DOI: 10.1016/j.ccell.2024.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 03/29/2024] [Accepted: 04/09/2024] [Indexed: 05/05/2024]
Abstract
Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK.
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MESH Headings
- Humans
- Glucocorticoids/pharmacology
- Receptors, Antigen, B-Cell/metabolism
- Animals
- Signal Transduction/drug effects
- Receptors, Glucocorticoid/metabolism
- Mice
- Cell Line, Tumor
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/metabolism
- Burkitt Lymphoma/drug therapy
- Burkitt Lymphoma/genetics
- Burkitt Lymphoma/metabolism
- Burkitt Lymphoma/pathology
- Molecular Targeted Therapy/methods
- Phosphatidylinositol 3-Kinases/metabolism
- src-Family Kinases/metabolism
- Gene Expression Regulation, Neoplastic/drug effects
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Affiliation(s)
- Jaewoo Choi
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Michele Ceribelli
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
| | - James D Phelan
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Björn Häupl
- Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60528 Frankfurt am Main, Germany
| | - Da Wei Huang
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - George W Wright
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tony Hsiao
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Vivian Morris
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Francesco Ciccarese
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata 64, 35128 Padova, Italy
| | - Boya Wang
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sean Corcoran
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sebastian Scheich
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60528 Frankfurt am Main, Germany; University Cancer Center (UCT) Frankfurt, University Hospital, Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany
| | - Xin Yu
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Weihong Xu
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yandan Yang
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Hong Zhao
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Joyce Zhou
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Grace Zhang
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jagan Muppidi
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Giorgio G Inghirami
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Thomas Oellerich
- Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60528 Frankfurt am Main, Germany
| | - Wyndham H Wilson
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Craig J Thomas
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Louis M Staudt
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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5
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Rowland MB, Moore PE, Correll RN. Regulation of cardiac fibroblast cell death by unfolded protein response signaling. Front Physiol 2024; 14:1304669. [PMID: 38283278 PMCID: PMC10811265 DOI: 10.3389/fphys.2023.1304669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 12/21/2023] [Indexed: 01/30/2024] Open
Abstract
The endoplasmic reticulum (ER) is a tightly regulated organelle that requires specific environmental properties to efficiently carry out its function as a major site of protein synthesis and folding. Embedded in the ER membrane, ER stress sensors inositol-requiring enzyme 1 (IRE1), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) serve as a sensitive quality control system collectively known as the unfolded protein response (UPR). In response to an accumulation of misfolded proteins, the UPR signals for protective mechanisms to cope with the cellular stress. Under prolonged unstable conditions and an inability to regain homeostasis, the UPR can shift from its original adaptive response to mechanisms leading to UPR-induced apoptosis. These UPR signaling pathways have been implicated as an important feature in the development of cardiac fibrosis, but identifying effective treatments has been difficult. Therefore, the apoptotic mechanisms of UPR signaling in cardiac fibroblasts (CFs) are important to our understanding of chronic fibrosis in the heart. Here, we summarize the maladaptive side of the UPR, activated downstream pathways associated with cell death, and agents that have been used to modify UPR-induced apoptosis in CFs.
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Affiliation(s)
- Mary B. Rowland
- Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, United States
| | - Patrick E. Moore
- Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, United States
| | - Robert N. Correll
- Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, United States
- Center for Convergent Bioscience and Medicine, University of Alabama, Tuscaloosa, AL, United States
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6
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Yusupova M, Ankawa R, Yosefzon Y, Meiri D, Bachelet I, Fuchs Y. Apoptotic dysregulation mediates stem cell competition and tissue regeneration. Nat Commun 2023; 14:7547. [PMID: 37985759 PMCID: PMC10662150 DOI: 10.1038/s41467-023-41684-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 09/14/2023] [Indexed: 11/22/2023] Open
Abstract
Since adult stem cells are responsible for replenishing tissues throughout life, it is vital to understand how failure to undergo apoptosis can dictate stem cell behavior both intrinsically and non-autonomously. Here, we report that depletion of pro-apoptotic Bax protein bestows hair follicle stem cells with the capacity to eliminate viable neighboring cells by sequestration of TNFα in their membrane. This in turn induces apoptosis in "loser" cells in a contact-dependent manner. Examining the underlying mechanism, we find that Bax loss-of-function competitive phenotype is mediated by the intrinsic activation of NFκB. Notably, winner stem cells differentially respond to TNFα, owing to their elevated expression of TNFR2. Finally, we report that in vivo depletion of Bax results in an increased stem cell pool, accelerating wound-repair and de novo hair follicle regeneration. Collectively, we establish a mechanism of mammalian cell competition, which can have broad therapeutic implications for tissue regeneration and tumorigenesis.
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Affiliation(s)
- Marianna Yusupova
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | - Roi Ankawa
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
- Augmanity, Rehovot, Israel
| | - Yahav Yosefzon
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | - David Meiri
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | | | - Yaron Fuchs
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
- Augmanity, Rehovot, Israel.
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7
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Sha G, Jiang Z, Zhang W, Jiang C, Wang D, Tang D. The multifunction of HSP70 in cancer: Guardian or traitor to the survival of tumor cells and the next potential therapeutic target. Int Immunopharmacol 2023; 122:110492. [PMID: 37390645 DOI: 10.1016/j.intimp.2023.110492] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/22/2023] [Accepted: 06/09/2023] [Indexed: 07/02/2023]
Abstract
Heat shock protein 70 (HSP70) is a highly conserved protein composed of nucleotide-binding domains (NBD) and C-terminal substrate binding domain (SBD) that can function as a "molecular chaperone". HSP70 was discovered to directly or indirectly play a regulatory role in both internal and external apoptosis pathways. Studies have shown that HSP70 can not only promote tumor progression, enhance tumor cell resistance and inhibit anticancer effects but also induce an anticancer response by activating immune cells. In addition, chemotherapy, radiotherapy and immunotherapy for cancer may be affected by HSP70, which has shown promising potential as an anticancer drug. In this review, we summarized the molecular structure and mechanism of HSP70 and discussed the dual effects of HSP70 on tumor cells and the possibility and potential methods of using HSP70 as a target to treat cancer.
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Affiliation(s)
- Gengyu Sha
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province 225000, China.
| | - Zhengting Jiang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province 225000, China.
| | - Wenjie Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province 225000, China.
| | - Chuwen Jiang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province 225000, China.
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou 225000, China.
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou 225000, China.
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8
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Clain JA, Boutrais S, Dewatines J, Racine G, Rabezanahary H, Droit A, Zghidi-Abouzid O, Estaquier J. Lipid metabolic reprogramming of hepatic CD4 + T cells during SIV infection. Microbiol Spectr 2023; 11:e0168723. [PMID: 37656815 PMCID: PMC10581067 DOI: 10.1128/spectrum.01687-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/24/2023] [Indexed: 09/03/2023] Open
Abstract
While liver inflammation is associated with AIDS, little is known so far about hepatic CD4+ T cells. By using the simian immunodeficiency virus (SIV)-infected rhesus macaque (RM) model, we aimed to characterize CD4+ T cells. The phenotype of CD4+ T cells was assessed by flow cytometry from uninfected (n = 3) and infected RMs, with either SIVmac251 (n = 6) or SHIVSF162p3 (n = 6). After cell sorting of hepatic CD4+ T cells, viral DNA quantification and RNA sequencing were performed.Thus, we demonstrated that liver CD4+ T cells strongly expressed the SIV coreceptor, CCR5. We showed that viremia was negatively correlated with the percentage of hepatic effector memory CD4+ T cells. Consistent with viral sensing, inflammatory and interferon gene transcripts were increased. We also highlighted the presence of harmful CD4+ T cells expressing GZMA and members of TGFB that could contribute to fuel inflammation and fibrosis. Whereas RNA sequencing demonstrated activated CD4+ T cells displaying higher levels of mitoribosome and membrane lipid synthesis transcripts, few genes were related to glycolysis and oxidative phosphorylation, which are essential to sustain activated T cells. Furthermore, we observed lower levels of mitochondrial DNA and higher levels of genes associated with damaged organelles (reticulophagy and mitophagy). Altogether, our data revealed that activated hepatic CD4+ T cells are reprogrammed to lipid metabolism. Thus, strategies aiming to reprogram T cell metabolism with effector function could be of interest for controlling viral infection and preventing liver disorders.IMPORTANCEHuman immunodeficiency virus (HIV) infection may cause liver diseases, associated with inflammation and tissue injury, contributing to comorbidity in people living with HIV. Paradoxically, the contribution of hepatic CD4+ T cells remains largely underestimated. Herein, we used the model of simian immunodeficiency virus (SIV)-infected rhesus macaques to access liver tissue. Our work demonstrates that hepatic CD4+ T cells express CCR5, the main viral coreceptor, and are infected. Viral infection is associated with the presence of inflamed and activated hepatic CD4+ T cells expressing cytotoxic molecules. Furthermore, hepatic CD4+ T cells are reprogrammed toward lipid metabolism after SIV infection. Altogether, our findings shed new light on hepatic CD4+ T cell profile that could contribute to liver injury following viral infection.
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Affiliation(s)
- Julien A. Clain
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
| | - Steven Boutrais
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
| | - Juliette Dewatines
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
| | - Gina Racine
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
| | | | - Arnaud Droit
- Proteomics Platform, CHU de Québec - Université Laval Research Center, Québec City, Québec, Canada
- Computational Biology Laboratory, CHU de Québec - Université Laval Research Center, Québec City, Québec, Canada
| | - Ouafa Zghidi-Abouzid
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
| | - Jérôme Estaquier
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
- INSERM U1124, Université Paris, Paris, France
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9
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Oliveira RC, Gama J, Casanova J. B-cell lymphoma 2 family members and sarcomas: a promising target in a heterogeneous disease. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:583-599. [PMID: 37720343 PMCID: PMC10501895 DOI: 10.37349/etat.2023.00154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 04/14/2023] [Indexed: 09/19/2023] Open
Abstract
Targeting the B-cell lymphoma 2 (Bcl-2) family proteins has been the backbone for hematological malignancies with overall survival improvements. The Bcl-2 family is a major player in apoptosis regulation and, has captured the researcher's interest in the treatment of solid tumors. Sarcomas are a heterogeneous group of diseases, comprising several entities, with high morbidity and mortality and with few specific therapies available. The treatment for sarcomas is based on platinum regimens, with variable results and poor outcomes, especially in advanced lesions. The high number of different sarcoma entities makes treatment standardization as well as the performance of clinical trials difficult. The use of Bcl-2 family members modifiers has revealed promising results in in vitro and in vivo models and may be a valid option, especially when used in combination with chemotherapy. In this article, a revision of these results and possibilities for the use of Bcl-2 family members inhibitors in sarcomas was performed.
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Affiliation(s)
- Rui Caetano Oliveira
- Centro de Anatomia Patológica Germano de Sousa, 3000 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR), 3000 Coimbra, Portugal
- Centre of Investigation on Genetics and Oncobiology (CIMAGO), 3000 Coimbra, Portugal
| | - João Gama
- Pathology Department, Centro Hospitalar e Universitário de Coimbra, 3000 Coimbra, Portugal
| | - José Casanova
- Centre of Investigation on Genetics and Oncobiology (CIMAGO), 3000 Coimbra, Portugal
- Orthopedic Oncology Department, Centro Hospitalar e Universitário de Coimbra, 3000 Coimbra, Portugal
- Faculdade de Medicina da Universidade de Coimbra, 3000 Coimbra, Portugal
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10
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Sarkar A, Paul A, Banerjee T, Maji A, Saha S, Bishayee A, Maity TK. Therapeutic advancements in targeting BCL-2 family proteins by epigenetic regulators, natural, and synthetic agents in cancer. Eur J Pharmacol 2023; 944:175588. [PMID: 36791843 DOI: 10.1016/j.ejphar.2023.175588] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 01/21/2023] [Accepted: 02/08/2023] [Indexed: 02/17/2023]
Abstract
Cancer is amongst the deadliest and most disruptive disorders, having a much higher death rate than other diseases worldwide. Human cancer rates continue to rise, thereby posing the most significant concerns for medical health professionals. In the last two decades, researchers have gone past several milestones in tackling cancer while gaining insight into the role of apoptosis in cancer or targeting various biomarker tools for prognosis and diagnosis. Apoptosis which is still a topic full of complexities, can be controlled considerably by B-cell lymphoma 2 (BCL-2) and its family members. Therefore, targeting proteins of this family to prevent tumorigenesis, is essential to focus on the pharmacological features of the anti-apoptotic and pro-apoptotic members, which will help to develop and manage this disorder. This review deals with the advancements of various epigenetic regulators to target BCL-2 family proteins, including the mechanism of several microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Similarly, a rise in natural and synthetic molecules' research over the last two decades has allowed us to acquire insights into understanding and managing the transcriptional alterations that have led to apoptosis and treating various neoplastic diseases. Furthermore, several inhibitors targeting anti-apoptotic proteins and inducers or activators targeting pro-apoptotic proteins in preclinical and clinical stages have been summarized. Overall, agonistic and antagonistic mechanisms of BCL-2 family proteins conciliated by epigenetic regulators, natural and synthetic agents have proven to be an excellent choice in developing cancer therapeutics.
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Affiliation(s)
- Arnab Sarkar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Abhik Paul
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Tanmoy Banerjee
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Avik Maji
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Sanjukta Saha
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
| | - Tapan Kumar Maity
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
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11
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Negligible role of TRAIL death receptors in cell death upon endoplasmic reticulum stress in B-cell malignancies. Oncogenesis 2023; 12:6. [PMID: 36755015 PMCID: PMC9908905 DOI: 10.1038/s41389-023-00450-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 01/20/2023] [Accepted: 01/25/2023] [Indexed: 02/10/2023] Open
Abstract
Impairments in protein folding in the endoplasmic reticulum (ER) lead to a condition called ER stress, which can trigger apoptosis via the mitochondrial or the death receptor (extrinsic) pathway. There is controversy concerning involvement of the death receptor (DR)4 and DR5-Caspase-8 -Bid pathway in ER stress-mediated cell death, and this axis has not been fully studied in B-cell malignancies. Using three B-cell lines from Mantle Cell Lymphoma, Waldenström's macroglobulinemia and Multiple Myeloma origins, we engineered a set of CRISPR KOs of key components of these cell death pathways to address this controversy. We demonstrate that DR4 and/or DR5 are essential for killing via TRAIL, however, they were dispensable for ER-stress induced-cell death, by Thapsigargin, Brefeldin A or Bortezomib, as were Caspase-8 and Bid. In contrast, the deficiency of Bax and Bak fully protected from ER stressors. Caspase-8 and Bid were cleaved upon ER-stress stimulation, but this was DR4/5 independent and rather a result of mitochondrial-induced feedback loop subsequent to Bax/Bak activation. Finally, combined activation of the ER-stress and TRAIL cell-death pathways was synergistic with putative clinical relevance for B-cell malignancies.
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12
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Bonsignore G, Martinotti S, Ranzato E. Endoplasmic Reticulum Stress and Cancer: Could Unfolded Protein Response Be a Druggable Target for Cancer Therapy? Int J Mol Sci 2023; 24:ijms24021566. [PMID: 36675080 PMCID: PMC9865308 DOI: 10.3390/ijms24021566] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/04/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Unfolded protein response (UPR) is an adaptive response which is used for re-establishing protein homeostasis, and it is triggered by endoplasmic reticulum (ER) stress. Specific ER proteins mediate UPR activation, after dissociation from chaperone Glucose-Regulated Protein 78 (GRP78). UPR can decrease ER stress, producing an ER adaptive response, block UPR if ER homeostasis is restored, or regulate apoptosis. Some tumour types are linked to ER protein folding machinery disturbance, highlighting how UPR plays a pivotal role in cancer cells to keep malignancy and drug resistance. In this review, we focus on some molecules that have been revealed to target ER stress demonstrating as UPR could be a new target in cancer treatment.
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13
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Rotimi DE, Singh SK. Interaction between apoptosis and autophagy in testicular function. Andrologia 2022; 54:e14602. [PMID: 36161318 DOI: 10.1111/and.14602] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/19/2022] [Accepted: 09/10/2022] [Indexed: 11/27/2022] Open
Abstract
Several processes including oxidative stress, apoptosis, inflammation and autophagy are related to testicular function. Recent studies indicate that a crosstalk between apoptosis and autophagy is essential in regulating testicular function. Autophagy and apoptosis communicate with each other in a complex way, allowing them to work for or against each other in testicular cell survival and death. Several xenobiotics especially endocrine-disrupting chemicals (EDCs) have caused reproductive toxicity because of their potential to modify the rate of autophagy and trigger apoptosis. Therefore, the purpose of the present review was to shed light on how autophagy and apoptosis interact together in the testis.
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Affiliation(s)
- Damilare E Rotimi
- SDG 03 Group - Good Health & Well-being, Landmark University, Omu-Aran, Nigeria.,Department of Biochemistry, Medicinal Biochemistry, Nanomedicine & Toxicology Laboratory, Landmark University, Omu-Aran, Nigeria
| | - Shio Kumar Singh
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, India
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14
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The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival. Cell Mol Life Sci 2022; 79:524. [PMID: 36123565 PMCID: PMC9485191 DOI: 10.1007/s00018-022-04541-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/20/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022]
Abstract
Endometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.
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15
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Wang Z, Zhang D, Yi XZ, Zhao Y, Yu A. Effects of regenerative peripheral nerve interface on dorsal root ganglia neurons following peripheral axotomy. Front Neurosci 2022; 16:914344. [PMID: 36161173 PMCID: PMC9489947 DOI: 10.3389/fnins.2022.914344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/15/2022] [Indexed: 12/05/2022] Open
Abstract
Background Long-term delayed reconstruction of injured peripheral nerves always results in poor recovery. One important reason is retrograde cell death among injured sensory neurons of dorsal root ganglia (DRG). A regenerative peripheral nerve interface (RPNI) was capable of generating new synaptogenesis between the proximal nerve stump and free muscle graft. Meanwhile, sensory receptors within the skeletal muscle can also be readily reinnervated by donor sensory axons, which allows the target muscles to become sources of sensory information for function reconstruction. To date, the effect of RPNI on injured sensory neurons is still unclear. Here, we aim to investigate the potential neuroprotective role of RPNI on sensory DRG neurons after sciatic axotomy in adult rats. Materials and methods The sciatic nerves of sixty rats were transected. The rats were randomly divided into three groups following this nerve injury: no treatment (control group, n = 20), nerve stump implantation inside a fully innervated muscle (NSM group, n = 20), or nerve stump implantation inside a free muscle graft (RPNI group, n = 20). At 8 weeks post-axotomy, ipsilateral L4 and L5 DRGs were harvested in each group. Toluidine blue staining was employed to quantify the neuronal densities in DRGs. The neuronal apoptosis index was quantified with TUNEL assay. Western blotting was applied to measure the expressions of Bax, Bcl-2, and neurotrophins (NTs) in ipsilateral DRGs. Results There were significantly higher densities of neurons in ipsilateral DRGs of RPNI group than NSM and control groups at 8 weeks post-axotomy (p < 0.01). Meanwhile, neuronal apoptosis index and the expressions of pro-apoptotic Bax within the ipsilateral DRGs were significantly lower in the RPNI group than those in the control and NSM groups (p < 0.05), while the opposite result was observed in the expression of pro-survival Bcl-2. Furthermore, the expressions of NGF, NT-3, BDNF, and GDNF were also upregulated in the ipsilateral DRGs in the RPNI group (p < 0.01). Conclusion The present results demonstrate that RPNI could prevent neuronal loss after peripheral axotomy. And the neuroprotection effect has a relationship with the upregulation of NTs in DRGs, such as NGF, NT-3, BDNF, and GDNF. These findings provide an effective therapy for neuroprotection in the delayed repair of the peripheral nerve injury.
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16
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Önder GÖ, Sezer G, Özdamar S, Yay A. Melatonin has an inhibitory effect on MCF‐7 and MDA‐MB‐231 human breast cancer cell lines by inducing autophagy and apoptosis. Fundam Clin Pharmacol 2022; 36:1038-1056. [DOI: 10.1111/fcp.12813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/07/2022] [Accepted: 06/30/2022] [Indexed: 12/19/2022]
Affiliation(s)
- Gözde Özge Önder
- Faculty of Medicine, Department of Histology and Embryology Erciyes University Kayseri Turkey
- Genome and Stem Cell Center Erciyes University Kayseri Turkey
| | - Gülay Sezer
- Genome and Stem Cell Center Erciyes University Kayseri Turkey
- Faculty of Medicine, Department of Pharmacology Erciyes University Kayseri Turkey
| | - Saim Özdamar
- Faculty of Medicine, Department of Histology and Embryology Pamukkale University Denizli Turkey
| | - Arzu Yay
- Faculty of Medicine, Department of Histology and Embryology Erciyes University Kayseri Turkey
- Genome and Stem Cell Center Erciyes University Kayseri Turkey
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17
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Guedes JP, Baptista V, Santos-Pereira C, Sousa MJ, Manon S, Chaves SR, Côrte-Real M. Acetic acid triggers cytochrome c release in yeast heterologously expressing human Bax. Apoptosis 2022; 27:368-381. [PMID: 35362903 DOI: 10.1007/s10495-022-01717-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2022] [Indexed: 11/29/2022]
Abstract
Proteins of the Bcl-2 protein family, including pro-apoptotic Bax and anti-apoptotic Bcl-xL, are critical for mitochondrial-mediated apoptosis regulation. Since yeast lacks obvious orthologs of Bcl-2 family members, heterologous expression of these proteins has been used to investigate their molecular and functional aspects. Active Bax is involved in the formation of mitochondrial outer membrane pores, through which cytochrome c (cyt c) is released, triggering a cascade of downstream apoptotic events. However, when in its inactive form, Bax is largely cytosolic or weakly bound to mitochondria. Given the central role of Bax in apoptosis, studies aiming to understand its regulation are of paramount importance towards its exploitation as a therapeutic target. So far, studies taking advantage of heterologous expression of human Bax in yeast to unveil regulation of Bax activation have relied on the use of artificial mutated or mitochondrial tagged Bax for its activation, rather than the wild type Bax (Bax α). Here, we found that cell death could be triggered in yeast cells heterologoulsy expressing Bax α with concentrations of acetic acid that are not lethal to wild type cells. This was associated with Bax mitochondrial translocation and cyt c release, closely resembling the natural Bax function in the cellular context. This regulated cell death process was reverted by co-expression with Bcl-xL, but not with Bcl-xLΔC, and in the absence of Rim11p, the yeast ortholog of mammalian GSK3β. This novel system mimics human Bax α regulation by GSK3β and can therefore be used as a platform to uncover novel Bax regulators and explore its therapeutic modulation.
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Affiliation(s)
- Joana P Guedes
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.,Centro de Investigacíon Médica Aplicada (CIMA), Universidad de Navarra, 31008, Pamplona, Spain
| | - Vitória Baptista
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.,Microelectromechanical Systems Research Unit (CMEMS-UMinho), School of Engineering, University of Minho, Campus de Azurém, 4800-058, Guimarães, Portugal.,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Cátia Santos-Pereira
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.,Centre of Biological Engineering (CEB), Department of Biological Engineering, University of Minho, 4710-057, Braga, Portugal.,LABBELS - Associate Laboratory, Braga, Guimarães, Portugal
| | - Maria João Sousa
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal
| | - Stéphen Manon
- UMR 5095, CNRS, Université de Bordeaux, Campus Carreire, 1 Rue Camille Saint-Saëns, 33077, Bordeaux, France
| | - Susana R Chaves
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal
| | - Manuela Côrte-Real
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.
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18
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Cebeci E, Yüksel B, Şahin F. Anti-cancer effect of boron derivatives on small-cell lung cancer. J Trace Elem Med Biol 2022; 70:126923. [PMID: 35007916 DOI: 10.1016/j.jtemb.2022.126923] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 12/08/2021] [Accepted: 01/03/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Anti-cancer activity of boron has been reported. Although many boron derivatives such as boric acid (BA) have been discovered to have anticancer effects, there are many boron derivatives whose anticancer effects have not yet been discovered. Some of these include sodium pentaborate pentahydrate (NaB), which has had limited research on its anticancer effects, and sodium perborate tetrahydrate (SPT), whose anticancer effect has yet to be discovered. The aim of this study was to investigate the anti-cancer effects of boric acid (BA), sodium pentaborate pentahydrate (NaB), and sodium perborate tetrahydrate (SPT) against small-cell lung cancer (SCLC) cell line DMS-114 cells in vitro. METHODS EC50 concentrations and effects of BA, NaB, and SPT on cell survival were detected with an MTS assay. The colony-forming unit (CFU) assay was used to assess their effects on cell colony formation capability. Their effects on apoptosis were determined by an Annexin-V assay. A cell cycle analysis was performed to understand at what phase the cell cycle is arrested. Real-Time PCR (RT-PCR) was used to evaluate the mRNA levels of apoptotic, anti-apoptotic, and tumor suppressor genes. Western blotting was used to determine the protein levels of p53 and Caspase 3. RESULTS The survival rates of DMS-114 cells decreased with BA, NaB and SPT after 72 h of treatment and the EC50 concentrations of DMS-114 and MRC-5 cells differed 5.5-fold in BA treatment, 5,2-fold in NaB treatment and 10-fold in SPT treatment. Colony unit numbers were decreased from 350 to 128, from 320 to 95, and from 430 to 96 in the BA, NaB, and SPT treatment groups, respectively. The apoptosis increased by 10, 19, and 42 percent after treatment with BA, NaB, and SPT for 72 h, respectively. Following 72 h of treatment with BA, NaB, and SPT, some pro-apoptotic and tumor suppressor genes were upregulated and some anti-apoptotic genes were downregulated. Cell cycle arrests were detected at the G2/M phase in the BA, and NaB treatment groups and at the Sub-G1 phase in the SPT treatment group. The protein levels of P53 and Caspase 3 increased with BA, NaB and SPT treatment for 72 h. CONCLUSIONS BA, NaB and SPT show anti-cancer activity in the DMS-114 cell line without damaging MRC-5 cells, and some of the molecular mechanisms are involved in apoptosis and cell cycle arrest.
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Affiliation(s)
- Emre Cebeci
- Yeditepe University, Department of Genetics and Bioengineering, Faculty of Engineering, Istanbul, Turkey
| | - Büşra Yüksel
- Yeditepe University, Department of Genetics and Bioengineering, Faculty of Engineering, Istanbul, Turkey
| | - Fikrettin Şahin
- Yeditepe University, Department of Genetics and Bioengineering, Faculty of Engineering, Istanbul, Turkey
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19
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Zhuang J, Xie L, Zheng L. A Glimpse of Programmed Cell Death Among Bacteria, Animals, and Plants. Front Cell Dev Biol 2022; 9:790117. [PMID: 35223864 PMCID: PMC8866957 DOI: 10.3389/fcell.2021.790117] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/24/2021] [Indexed: 12/15/2022] Open
Abstract
Programmed cell death (PCD) in animals mainly refers to lytic and non-lytic forms. Disruption and integrity of the plasma membrane are considered as hallmarks of lytic and apoptotic cell death, respectively. These lytic cell death programs can prevent the hosts from microbial pathogens. The key to our understanding of these cases is pattern recognition receptors, such as TLRs in animals and LRR-RLKs in plants, and nod-like receptors (NLRs). Herein, we emphatically discuss the biochemical and structural studies that have clarified the anti-apoptotic and pro-apoptotic functions of Bcl-2 family proteins during intrinsic apoptosis and how caspase-8 among apoptosis, necroptosis, and pyroptosis sets the switchable threshold and integrates innate immune signaling, and that have compared the similarity and distinctness of the apoptosome, necroptosome, and inflammasome. We recapitulate that the necroptotic MLKL pore, pyroptotic gasdermin pore, HR-inducing resistosome, and mitochondrial Bcl-2 family all can form ion channels, which all directly boost membrane disruption. Comparing the conservation and unique aspects of PCD including ferrroptosis among bacteria, animals, and plants, the commonly shared immune domains including TIR-like, gasdermin-like, caspase-like, and MLKL/CC-like domains act as arsenal modules to restructure the diverse architecture to commit PCD suicide upon stresses/stimuli for host community.
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Affiliation(s)
- Jun Zhuang
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Agriculture and Forestry University, Fuzhou, China
- Institute of Plant Virology, Fujian Agriculture and Forestry University, Fuzhou, China
- *Correspondence: Jun Zhuang,
| | - Li Xie
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Agriculture and Forestry University, Fuzhou, China
- Institute of Plant Virology, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Luping Zheng
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Agriculture and Forestry University, Fuzhou, China
- Institute of Plant Virology, Fujian Agriculture and Forestry University, Fuzhou, China
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20
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Mora-Molina R, Stöhr D, Rehm M, López-Rivas A. cFLIP downregulation is an early event required for endoplasmic reticulum stress-induced apoptosis in tumor cells. Cell Death Dis 2022; 13:111. [PMID: 35115486 PMCID: PMC8813907 DOI: 10.1038/s41419-022-04574-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 12/30/2021] [Accepted: 01/20/2022] [Indexed: 12/31/2022]
Abstract
Protein misfolding or unfolding and the resulting endoplasmic reticulum (ER) stress frequently occur in highly proliferative tumors. How tumor cells escape cell death by apoptosis after chronic ER stress remains poorly understood. We have investigated in both two-dimensional (2D) cultures and multicellular tumor spheroids (MCTSs) the role of caspase-8 inhibitor cFLIP as a regulator of the balance between apoptosis and survival in colon cancer cells undergoing ER stress. We report that downregulation of cFLIP proteins levels is an early event upon treatment of 2D cultures of colon cancer cells with ER stress inducers, preceding TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) upregulation, caspase-8 activation, and apoptosis. Maintaining high cFLIP levels during ER stress by ectopic expression of cFLIP markedly inhibits ER stress-induced caspase-8 activation and apoptosis. Conversely, cFLIP knockdown by RNA interference significantly accelerates caspase-8 activation and apoptosis upon ER stress. Despite activation of the proapoptotic PERK branch of the unfolded protein response (UPR) and upregulation of TRAIL-R2, MCTSs are markedly more resistant to ER stress than 2D cultures of tumor cells. Resistance of MCTSs to ER stress-induced apoptosis correlates with sustained cFLIPL expression. Interestingly, resistance to ER stress-induced apoptosis is abolished in MCTSs generated from cFLIPL knockdown tumor cells. Overall, our results suggest that controlling cFLIP levels in tumors is an adaptive strategy to prevent tumor cell's demise in the unfavorable conditions of the tumor microenvironment.
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Affiliation(s)
- Rocío Mora-Molina
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Avda Américo Vespucio 24, 41092, Sevilla, Spain
| | - Daniela Stöhr
- University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany
| | - Markus Rehm
- University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany
| | - Abelardo López-Rivas
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Avda Américo Vespucio 24, 41092, Sevilla, Spain. .,Centro de Investigación Biomédica en Red-Oncología (CIBERONC), Carlos III Health Institute, Seville, Spain.
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21
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Dai H, Meng XW, Ye K, Jia J, Kaufmann SH. Therapeutics targeting BCL2 family proteins. MECHANISMS OF CELL DEATH AND OPPORTUNITIES FOR THERAPEUTIC DEVELOPMENT 2022:197-260. [DOI: 10.1016/b978-0-12-814208-0.00007-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Kalimuthu K, Kim JH, Park YS, Luo X, Zhang L, Ku JL, Choudry MHA, Lee YJ. Glucose deprivation-induced endoplasmic reticulum stress response plays a pivotal role in enhancement of TRAIL cytotoxicity. J Cell Physiol 2021; 236:6666-6677. [PMID: 33586156 PMCID: PMC11572546 DOI: 10.1002/jcp.30329] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 02/02/2021] [Accepted: 02/04/2021] [Indexed: 12/12/2022]
Abstract
Abnormalities of the tumor vasculature result in insufficient blood supply and development of a tumor microenvironment that is characterized by low glucose concentrations, low extracellular pH, and low oxygen tensions. We previously reported that glucose-deprived conditions induce metabolic stress and promote tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cytotoxicity. In this study, we examined whether the metabolic stress-associated endoplasmic reticulum (ER) stress response pathway plays a pivotal role in the enhancement of TRAIL cytotoxicity. We observed no significant cytotoxicity when human colorectal cancer SW48 cells were treated with various doses of TRAIL (2-100 ng/ml) for 4 h or glucose (0-25 mM) for 24 h. However, a combination of TRAIL and low glucose-induced dose-dependent apoptosis through activation of caspases (-8, -9, and -3). Studies with activating transcription factor 4 (ATF4), C/EBP-homologous protein (CHOP), p53 upregulated modulator of apoptosis (PUMA), or death receptor 5 (DR5)-deficient mouse embryonic fibroblasts or HCT116 cells suggest that the ATF4-CHOP-PUMA axis and the ATF4-CHOP-DR5 axis are involved in the combined treatment-induced apoptosis. Moreover, the combined treatment-induced apoptosis was completely suppressed in BH3 interacting-domain death agonist (Bid)- or Bcl-2-associated X protein (Bax)-deficient HCT116 cells, but not Bak-deficient HCT116 cells. Interestingly, the combined treatment-induced Bax oligomerization was suppressed in PUMA-deficient HCT116 cells. These results suggest that glucose deprivation enhances TRAIL-induced apoptosis by integrating the ATF4-CHOP-PUMA axis and the ATF4-CHOP-DR5 axis, consequently amplifying the Bid-Bax-associated mitochondria-dependent pathway.
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Affiliation(s)
- Kalishwaralal Kalimuthu
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jin Hong Kim
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yong Seok Park
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Xu Luo
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Lin Zhang
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ja-Lok Ku
- Department of Biomedical Sciences/Department of Medicine, Laboratory of Cell Biology, Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - M. Haroon A. Choudry
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yong J. Lee
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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23
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Pan H, Song T, Wang Z, Guo Y, Zhang H, Ji T, Cao K, Zhang Z. Ectopic BH3-only protein Bim acts as a co-chaperone to positively regulate Hsp70 in yeast. J Biochem 2021; 170:539-545. [PMID: 34185080 DOI: 10.1093/jb/mvab073] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 06/08/2021] [Indexed: 11/12/2022] Open
Abstract
The chaperone heat shock protein 70 (Hsp70) is conserved from bacteria to humans and is crucial for avoiding protein misfolding under stress. Bim functions mainly as one of the Bcl-2 family pro-apoptotic members, was identified to be a co-chaperone of Hsp70. Herein, we reported that ectopic Bim could constitute the interactions with intrinsic Hsp70 and translate its positive co-chaperone activity in vitro to the yeast growth promotion and help Hsp70 to fold its client Ras-like protein. With the help of a specific Hsp70/Bim disruptor, we illustrated that Hsp70/Bim dimers rescue yeast from heat shock. In an organism lacks apoptotic Bcl-2 factors, the pro-apoptotic Bim in mammalian cells exhibits pro-survival functions.
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Affiliation(s)
- Hao Pan
- State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China
| | - Ting Song
- State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China
| | - Ziqian Wang
- State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China
| | - Yafei Guo
- School of Life Science and Technology, Dalian University of Technology, Dalian, China
| | - Hong Zhang
- School of Life Science and Technology, Dalian University of Technology, Dalian, China
| | - Tong Ji
- State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China
| | - Keke Cao
- State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China
| | - Zhichao Zhang
- State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China
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24
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Intrinsically Connected: Therapeutically Targeting the Cathepsin Proteases and the Bcl-2 Family of Protein Substrates as Co-regulators of Apoptosis. Int J Mol Sci 2021; 22:ijms22094669. [PMID: 33925117 PMCID: PMC8124540 DOI: 10.3390/ijms22094669] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 12/14/2022] Open
Abstract
Taken with the growing importance of cathepsin-mediated substrate proteolysis in tumor biology and progression, the focus and emphasis placed on therapeutic design and development is coming into fruition. Underpinning this approach is the invariable progression from the direction of fully characterizing cathepsin protease members and their substrate targets, towards targeting such an interaction with tangible therapeutics. The two groups of such substrates that have gained much attention over the years are the pro- and anti- apoptotic protein intermediates from the extrinsic and intrinsic signaling arms of the apoptosis pathway. As proteins that are central to determining cellular fate, some of them present themselves as very favorable candidates for therapeutic targeting. However, considering that both anti- and pro- apoptotic signaling intermediates have been reported to be downstream substrates for certain activated cathepsin proteases, therapeutic targeting approaches based on greater selectivity do need to be given greater consideration. Herein, we review the relationships shared by the cathepsin proteases and the Bcl-2 homology domain proteins, in the context of how the topical approach of adopting 'BH3-mimetics' can be explored further in modulating the relationship between the anti- and pro- apoptotic signaling intermediates from the intrinsic apoptosis pathway and their upstream cathepsin protease regulators. Based on this, we highlight important future considerations for improved therapeutic design.
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Kung WM, Lin MS. Beneficial Impacts of Alpha-Eleostearic Acid from Wild Bitter Melon and Curcumin on Promotion of CDGSH Iron-Sulfur Domain 2: Therapeutic Roles in CNS Injuries and Diseases. Int J Mol Sci 2021; 22:3289. [PMID: 33804820 PMCID: PMC8037269 DOI: 10.3390/ijms22073289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 03/20/2021] [Accepted: 03/21/2021] [Indexed: 02/05/2023] Open
Abstract
Neuroinflammation and abnormal mitochondrial function are related to the cause of aging, neurodegeneration, and neurotrauma. The activation of nuclear factor κB (NF-κB), exaggerating these two pathologies, underlies the pathogenesis for the aforementioned injuries and diseases in the central nervous system (CNS). CDGSH iron-sulfur domain 2 (CISD2) belongs to the human NEET protein family with the [2Fe-2S] cluster. CISD2 has been verified as an NFκB antagonist through the association with peroxisome proliferator-activated receptor-β (PPAR-β). This protective protein can be attenuated under circumstances of CNS injuries and diseases, thereby causing NFκB activation and exaggerating NFκB-provoked neuroinflammation and abnormal mitochondrial function. Consequently, CISD2-elevating plans of action provide pathways in the management of various disease categories. Various bioactive molecules derived from plants exert protective anti-oxidative and anti-inflammatory effects and serve as natural antioxidants, such as conjugated fatty acids and phenolic compounds. Herein, we have summarized pharmacological characters of the two phytochemicals, namely, alpha-eleostearic acid (α-ESA), an isomer of conjugated linolenic acids derived from wild bitter melon (Momordica charantia L. var. abbreviata Ser.), and curcumin, a polyphenol derived from rhizomes of Curcuma longa L. In this review, the unique function of the CISD2-elevating effect of α-ESA and curcumin are particularly emphasized, and these natural compounds are expected to serve as a potential therapeutic target for CNS injuries and diseases.
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Affiliation(s)
- Woon-Man Kung
- Department of Exercise and Health Promotion, College of Kinesiology and Health, Chinese Culture University, Taipei 11114, Taiwan;
| | - Muh-Shi Lin
- Division of Neurosurgery, Department of Surgery, Kuang Tien General Hospital, Taichung 43303, Taiwan
- Department of Biotechnology and Animal Science, College of Bioresources, National Ilan University, Yilan 26047, Taiwan
- Department of Biotechnology, College of Medical and Health Care, Hung Kuang University, Taichung 43302, Taiwan
- Department of Health Business Administration, College of Medical and Health Care, Hung Kuang University, Taichung 43302, Taiwan
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Ke W, Zhao X, Lu Z. Foeniculum vulgare seed extract induces apoptosis in lung cancer cells partly through the down-regulation of Bcl-2. Biomed Pharmacother 2021; 135:111213. [PMID: 33395604 DOI: 10.1016/j.biopha.2020.111213] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 12/07/2020] [Accepted: 12/26/2020] [Indexed: 12/14/2022] Open
Abstract
The factors behind the pathogenesis of lung cancer are not clear, and treatment failure is generally caused by drug resistance, recurrence, and metastasis. Development of new therapeutic agents to overcome drug-resistance remains a challenge clinically. Various extracts of Foeniculum vulgare have shown promising anticancer activity; however, effects on lung cancer and the underlying molecular mechanisms of action are not clear. In the present study, we found that the ethanol extract of Foeniculum vulgare seeds (EEFS) significantly reduced lung cancer cell growth in vitro and in vivo. EEFS decreased the viability of and triggered apoptosis in the lung cancer cell lines NCI-H446 and NCI-H661. EEFS induced apoptosis mainly through inhibition of Bcl-2 protein expression, reduction of mitochondrial membrane potential, and release of Cytochrome C. Moreover, EEFS significantly inhibited colony formation and cell migration in lung cancer cells. EEFS also effectively inhibited the growth of xenograft tumors derived from NCI-446 cells by reducing Bcl-2 protein expression and inducing apoptosis. Taken together, these findings suggest that EEFS exerts anti-lung cancer activity by targeting the Bcl-2 protein and may have potential as a therapeutic drug for lung cancer.
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Affiliation(s)
- Weiwei Ke
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110004, LN, China
| | - Xiangxuan Zhao
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110004, LN, China.
| | - Zaiming Lu
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110004, LN, China.
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Al Dubayee M, Alshahrani A, Aljada D, Zahra M, Alotaibi A, Ababtain I, Alnaim M, Alahmari A, Aljarallah A, Elahi MA, Fakhoury HMA. Gene Expression Profiling of Apoptotic Proteins in Circulating Peripheral Blood Mononuclear Cells in Type II Diabetes Mellitus and Modulation by Metformin. Diabetes Metab Syndr Obes 2021; 14:1129-1139. [PMID: 33758522 PMCID: PMC7979348 DOI: 10.2147/dmso.s300048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 02/23/2021] [Indexed: 11/23/2022] Open
Abstract
INTRODUCTION Insulin resistance in obesity and type 2 diabetes mellitus (T2DM) is associated with cardiovascular complications such as atherosclerosis. On the other hand, the reduction of apoptosis in macrophages has been linked with accelerated atherosclerosis. Apoptosis is controlled by a different family of proteins including Bcl-2 and caspases. METHODS To examine apoptosis in insulin resistance, we assessed the mRNA expression by qRT-PCR of several Bcl-2 family members, as well as caspase-3, -7, -8, and -9 in peripheral blood mononuclear cells (PBMCs) isolated from lean, obese, diabetic, and diabetic on metformin individuals. RESULTS PBMCs of diabetic individuals exhibited reduced expression of caspase-7 and increased expression of Bcl-10, Bad, Bax, Bid, and caspase-3. T2DM on metformin group had significantly higher Bad, Bax, and caspase-7 expression. DISCUSSION The moderate up-regulation of pro-apoptotic Bcl-10, Bax, Bad, Bid, and the effector caspase-3 coupled with inhibition of caspase-7 in circulating PBMCs of T2DM could be the result of increased inflammation in T2DM. Metformin treatment significantly inhibited the expression of Bcl-10, Bid, and caspase-3 and upregulated Bad/Bax/caspase-7 pathway suggesting the activation of Bad/Bax/caspase-7 apoptotic pathway. Further studies are warranted to elicit the underlying apoptotic pathways of PBMCs in T2DM and following metformin treatment.
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Affiliation(s)
- Mohammed Al Dubayee
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia
- Department of Medicine, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
- Correspondence: Mohammed Al Dubayee College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), P.O. Box 22490, Riyadh, Saudi ArabiaTel +966 11 801 1111 ext: 53551 Email
| | - Awad Alshahrani
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia
- Department of Medicine, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
| | - Dana Aljada
- College of Liberal Arts and Sciences, Hofstra University, Hempstead, NY, USA
| | - Mahmoud Zahra
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Ahmed Alotaibi
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
| | - Ibrahim Ababtain
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
| | - Malik Alnaim
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
| | - Ali Alahmari
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
| | - Abdullah Aljarallah
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
| | - Muhammad Affan Elahi
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Hana M A Fakhoury
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Lin VS, Xu ZF, Huang DCS, Thijssen R. BH3 Mimetics for the Treatment of B-Cell Malignancies-Insights and Lessons from the Clinic. Cancers (Basel) 2020; 12:cancers12113353. [PMID: 33198338 PMCID: PMC7696913 DOI: 10.3390/cancers12113353] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/06/2020] [Accepted: 11/10/2020] [Indexed: 12/17/2022] Open
Abstract
Simple Summary B-cell malignancies, including chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and plasma cell dyscrasias, are significant contributors to cancer morbidity and mortality worldwide. The pathogenesis of many B-cell malignancies involves perturbations in the intrinsic pathway of apoptosis that allow cells to evade cell death. BH3 mimetics represent a class of anti-cancer agents that can restore the ability of cancer cells to undergo apoptosis. Venetoclax, a recently approved BH3 mimetic, has transformed the therapeutic landscape for CLL. Other BH3 mimetics are currently under development. This review summarizes the available data on existing BH3 mimetics and highlights both the rapidly expanding role of BH3 mimetics in the treatment of B-cell malignancies and the clinical challenges of their use. Abstract The discovery of the link between defective apoptotic regulation and cancer cell survival engendered the idea of targeting aberrant components of the apoptotic machinery for cancer therapy. The intrinsic pathway of apoptosis is tightly controlled by interactions amongst members of three distinct subgroups of the B-cell lymphoma 2 (BCL2) family of proteins. The pro-survival BCL2 proteins prevent apoptosis by keeping the pro-apoptotic effector proteins BCL2-associated X protein (BAX) and BCL2 homologous antagonist/killer (BAK) in check, while the BH3-only proteins initiate apoptosis by either neutralizing the pro-survival BCL2 proteins or directly activating the pro-apoptotic effector proteins. This tripartite regulatory mechanism is commonly perturbed in B-cell malignancies facilitating cell death evasion. Over the past two decades, structure-based drug discovery has resulted in the development of a series of small molecules that mimic the function of BH3-only proteins called the BH3 mimetics. The most clinically advanced of these is venetoclax, which is a highly selective inhibitor of BCL2 that has transformed the treatment landscape for chronic lymphocytic leukemia (CLL). Other BH3 mimetics, which selectively target myeloid cell leukemia 1 (MCL1) and B-cell lymphoma extra large (BCLxL), are currently under investigation for use in diverse malignancies. Here, we review the current role of BH3 mimetics in the treatment of CLL and other B-cell malignancies and address open questions in this rapidly evolving field.
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Affiliation(s)
- Victor S. Lin
- The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, 3052 Parkville, Australia; (V.S.L.); (Z.-F.X.); (D.C.S.H.)
- Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, 3000 Melbourne, Australia
| | - Zhuo-Fan Xu
- The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, 3052 Parkville, Australia; (V.S.L.); (Z.-F.X.); (D.C.S.H.)
- School of Medicine, Tsinghua University, 30 Shuangqing Road, Haidian District, Beijing 100084, China
| | - David C. S. Huang
- The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, 3052 Parkville, Australia; (V.S.L.); (Z.-F.X.); (D.C.S.H.)
- Department of Medical Biology, University of Melbourne, 3000 Melbourne, Australia
| | - Rachel Thijssen
- The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, 3052 Parkville, Australia; (V.S.L.); (Z.-F.X.); (D.C.S.H.)
- Department of Medical Biology, University of Melbourne, 3000 Melbourne, Australia
- Correspondence:
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Glucocorticoids can induce BIM to trigger apoptosis in the absence of BAX and BAK1. Cell Death Dis 2020; 11:442. [PMID: 32513923 PMCID: PMC7280233 DOI: 10.1038/s41419-020-2599-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 04/27/2020] [Accepted: 05/07/2020] [Indexed: 12/16/2022]
Abstract
Cells from two murine lymphoid lines died 24-48 h after treatment with the glucocorticoid dexamethasone. Deletion of Bax and Bak1 prevented rapid apoptosis, but treatment with dexamethasone for greater 6 days still led to cell death that was characterized by release of cytochrome c into the cytosol, activation of caspases, and loss of cell membrane integrity. In WEHI7 thymoma cells, this did not occur when Bcl2l11 (Bim) was deleted in addition to Bax and Bak1. When these triple mutant lines were exposed to dexamethasone for 10 days, they arrested, but after dexamethasone was removed, they had 10-fold higher clone forming efficiency than Bax/Bak1 double knock-out cells. Although induced over-expression of BIMs alone was not sufficient to induce the death of Bax-/-Bak1-/-Bim-/- cells, they did die when BIMs was induced in the presence of dexamethasone. These results suggest that dexamethasone induces production of BIM together with other, as yet unidentified proteins, that cause release of cytochrome c and apoptosis in the absence of BAX and BAK1.
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Poudel SB, Dixit M, Neginskaya M, Nagaraj K, Pavlov E, Werner H, Yakar S. Effects of GH/IGF on the Aging Mitochondria. Cells 2020; 9:cells9061384. [PMID: 32498386 PMCID: PMC7349719 DOI: 10.3390/cells9061384] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/25/2020] [Accepted: 05/26/2020] [Indexed: 12/11/2022] Open
Abstract
The mitochondria are key organelles regulating vital processes in the eukaryote cell. A decline in mitochondrial function is one of the hallmarks of aging. Growth hormone (GH) and the insulin-like growth factor-1 (IGF-1) are somatotropic hormones that regulate cellular homeostasis and play significant roles in cell differentiation, function, and survival. In mammals, these hormones peak during puberty and decline gradually during adulthood and aging. Here, we review the evidence that GH and IGF-1 regulate mitochondrial mass and function and contribute to specific processes of cellular aging. Specifically, we discuss the contribution of GH and IGF-1 to mitochondrial biogenesis, respiration and ATP production, oxidative stress, senescence, and apoptosis. Particular emphasis was placed on how these pathways intersect during aging.
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Affiliation(s)
- Sher Bahadur Poudel
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry New York, NY 10010–4086, USA; (S.B.P.); (M.D.); (M.N.); (E.P.)
| | - Manisha Dixit
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry New York, NY 10010–4086, USA; (S.B.P.); (M.D.); (M.N.); (E.P.)
| | - Maria Neginskaya
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry New York, NY 10010–4086, USA; (S.B.P.); (M.D.); (M.N.); (E.P.)
| | - Karthik Nagaraj
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; (K.N.); (H.W.)
| | - Evgeny Pavlov
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry New York, NY 10010–4086, USA; (S.B.P.); (M.D.); (M.N.); (E.P.)
| | - Haim Werner
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; (K.N.); (H.W.)
| | - Shoshana Yakar
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry New York, NY 10010–4086, USA; (S.B.P.); (M.D.); (M.N.); (E.P.)
- Correspondence: ; Tel.: +212-998-9721
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Garcia JS, Bhatt S, Fell G, Sperling AS, Burgess M, Keshishian H, Yilma B, Brunner A, Neuberg D, Carr SA, Ebert BL, Ballen K, Stone RM, DeAngelo DJ, Medeiros BC, Letai A. Increased mitochondrial apoptotic priming with targeted therapy predicts clinical response to re-induction chemotherapy. Am J Hematol 2020; 95:245-250. [PMID: 31804723 PMCID: PMC10683501 DOI: 10.1002/ajh.25692] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 11/30/2019] [Indexed: 02/06/2023]
Abstract
Most patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) do not benefit from current re-induction or approved targeted therapies. In the absence of targetable genetic mutations, there is minimal guidance on optimal treatment selection particularly in the R/R setting highlighting an unmet need for clinically useful functional biomarkers. Blood and bone marrow samples from patients treated on two clinical trials were used to test the combination of lenalidomide (LEN) and MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy in R/R AML patients. The bone marrow samples were available to test the clinical utility of the mitochondrial apoptotic BH3 and dynamic BH3 profiling (DBP) assays in predicting response, as there was no clear genetic biomarker identifying responders. To test whether LEN-induced mitochondrial priming predicted clinical response to LEN-MEC therapy, we performed DBP on patient myeloblasts. We found that short-term ex vivo treatment with lenalidomide discriminated clinical responders from non-responders based on drug-induced change in priming (delta priming). Using paired patient samples collected before and after clinical LEN treatment (prior to MEC dosing), we confirmed LEN-induced increased apoptotic priming in vivo, suggesting LEN enhanced vulnerability of myeloblasts to cytotoxic MEC chemotherapy. This is the first study demonstrating the potential role of DBP in predicting clinical response to a combination regimen. Our findings demonstrate that functional properties of relapsed AML can identify active therapies.
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Affiliation(s)
| | - Shruti Bhatt
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | | | - Michael Burgess
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | | | - Binyam Yilma
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | | | - Steven A. Carr
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | | | - Karen Ballen
- University of Virginia Health System, Charlottesville, Virginia
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Solà-Riera C, García M, Ljunggren HG, Klingström J. Hantavirus inhibits apoptosis by preventing mitochondrial membrane potential loss through up-regulation of the pro-survival factor BCL-2. PLoS Pathog 2020; 16:e1008297. [PMID: 32032391 PMCID: PMC7032725 DOI: 10.1371/journal.ppat.1008297] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 02/20/2020] [Accepted: 12/30/2019] [Indexed: 12/12/2022] Open
Abstract
Hantaviruses, zoonotic RNA viruses belonging to the order Bunyavirales, cause two severe acute diseases in humans, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Hantavirus-infected patients show strong cytotoxic lymphocyte responses and hyperinflammation; however, infected cells remain mostly intact. Hantaviruses were recently shown to inhibit apoptosis in infected cells. By inhibiting granzyme B- and TRAIL-mediated apoptosis, hantaviruses specifically and efficiently inhibit cytotoxic lymphocyte-mediated killing of infected cells. Hantaviruses also strongly inhibit apoptosis triggered intrinsically; i.e., initiated through intracellular activation pathways different from those used by cytotoxic lymphocytes. However, insights into the latter mechanisms are currently largely unknown. Here, we dissected the mechanism behind how hantavirus infection, represented by the HFRS-causing Hantaan virus and the HPS-causing Andes virus, results in resistance to staurosporine-induced apoptosis. Less active caspase-8 and caspase-9, and consequently less active caspase-3, was observed in infected compared to uninfected staurosporine-exposed cells. While staurosporine-exposed uninfected cells showed massive release of pro-apoptotic cytochrome C into the cytosol, this was not observed in infected cells. Further, hantaviruses prevented activation of BAX and mitochondrial outer membrane permeabilization (MOMP). In parallel, a significant increase in levels of the pro-survival factor BCL-2 was observed in hantavirus-infected cells. Importantly, direct inhibition of BCL-2 by the inhibitor ABT-737, as well as silencing of BCL-2 by siRNA, resulted in apoptosis in staurosporine-exposed hantavirus-infected cells. Overall, we here provide a tentative mechanism by which hantaviruses protect infected cells from intrinsic apoptosis at the mitochondrial level by inducing an increased expression of the pro-survival factor BCL-2, thereby preventing MOMPs and subsequent activation of caspases. The variety of mechanisms used by hantaviruses to ensure survival of infected cells likely contribute to the persistent infection in natural hosts and may play a role in immunopathogenesis of HFRS and HPS in humans. Hantaviruses cause two severe, often fatal, diseases in humans: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS; also called hantavirus cardiopulmonary syndrome (HCPS)). Two hallmarks of human hantavirus infection are robust immune cell activation and hyperinflammation. Despite these strong immune responses, hantavirus-infected cells do not succumb to cell death in patients. Recent studies have shown that hantaviruses hamper cytotoxic lymphocyte-mediated killing, by inhibiting cytotoxic granule-dependent induction of apoptosis and TRAIL-mediated apoptosis, as well as inhibiting intrinsic apoptosis. However, mechanisms behind hantavirus induced inhibition of intrinsic apoptosis have not been described. Here, we show that hantavirus infection leads to increased production of the anti-apoptotic protein BCL-2, hampering the permeabilization of mitochondria and thereby blocking downstream signaling and activation of caspases. Treatment of infected cells with a BCL-2 inhibitor, as well as silencing of BCL-2 with siRNA, both reverted the anti-apoptotic effect. Taken together, this study reveals new insights into the interactions between hantaviruses and infected cells and demonstrates novel mechanisms by which hantaviruses inhibit apoptosis by hampering the permeabilization of mitochondria.
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Affiliation(s)
- Carles Solà-Riera
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- * E-mail:
| | - Marina García
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Hans-Gustaf Ljunggren
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Jonas Klingström
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Luo L, Zhu S, Tong Y, Peng S. Ferulic Acid Induces Apoptosis of HeLa and Caski Cervical Carcinoma Cells by Down-Regulating the Phosphatidylinositol 3-Kinase (PI3K)/Akt Signaling Pathway. Med Sci Monit 2020; 26:e920095. [PMID: 31983729 PMCID: PMC7003662 DOI: 10.12659/msm.920095] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Background Ferulic acid is an antioxidant phenolic compound derived from plants, which has effects on cancer cells. This study aimed to investigate the effects of ferulic acid on HeLa and Caski human cervical carcinoma cells and the molecular mechanisms involved. Material/Methods HeLa and Caski human cervical carcinoma cells were grown in culture and treated with increasing doses of ferulic acid. The MTT assay was used to evaluate cell viability. Flow cytometry was performed with 4′,6-diamidino-2-phenylindole (DAPI) and Annexin V staining for cell apoptosis. The expression of myeloid leukemia cell differentiation-1 (Mcl-1) protein and MCL-1 mRNA were determined by Western blot and reverse transcription-polymerase chain reaction (RT-PCR). Results Ferulic acid significantly reduced HeLa and Caski cell viability in the concentration range of 4–20 μM (P<0.05). Ferulic acid treatment promoted DNA condensation and significantly increased apoptosis in Caski cells (P<0.05). Ferulic acid treatment resulted in the activation of pro-caspase-3, pro-caspase-8, pro-caspase-9, and PARP. The MTT assay showed that ferulic acid did not reduce the viability of Caski cells treated with the caspase inhibitor, z-VAD-fmk. Ferulic acid reduced the levels of Bcl-2 and Mcl-1, and increased the levels of Bax and reactive oxygen species (ROS). In Caski cells, Akt and PI3K phosphorylation were reduced by ferulic acid in a concentration-dependent manner. Conclusions The effects of ferulic acid were dose-dependent and resulted in cell cytotoxicity and apoptosis of HeLa and Caski cells, and the PI3K/Akt signaling pathway was down-regulated in Caski cells.
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Affiliation(s)
- Liping Luo
- Department of Obstetrics, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China (mainland)
| | - Sihong Zhu
- Department of Obstetrics and Gynecology, Jiangxi Health Vocational College, Nanchang, Jiangxi, China (mainland)
| | - Yan Tong
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China (mainland)
| | - Shiwei Peng
- Department of Obstetrics and Gynecology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, China (mainland)
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Han B, Wu J, Huang L. Induction of Apoptosis in Lung Cancer Cells by Viburnum grandiflorum via Mitochondrial Pathway. Med Sci Monit 2020; 26:e920265. [PMID: 31900380 PMCID: PMC6977709 DOI: 10.12659/msm.920265] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Background Lung cancer is one of the leading causes of mortality and morbidity. Viburnum grandiflorum is a medicinal herb known for its wide spectrum of pharmacological activities, but its anti-cancer properties against lung cancer cells have not been previously investigated. The present study elucidated the antitumor effect and associated mechanism of methanol extract of Viburnum grandiflorum extract (VGE) against lung cancer cells. Material/Methods The viability of H1650, HCC827, and H1299 cells was measured using MTT assay. Apoptosis and cell cycle progression were determined by flow cytometry using annexin-V/PI and JC-1 stains, respectively. The Lipofectamine Plus reagent (Invitrogen) was used for transfection of caspase-9 plasmid to H1650 and H1299 cells. Results The results showed decreased H1650, HCC827, and H1299 cell viability by VGE, which occurred in a concentration- and time-dependent manner. The VGE treatment significantly increased the rate of apoptosis in H1650 (P<0.05) and H1299 (P<0.02) cells at 48 and 72 h. Treatment of H1650 and H1299 cells with 10 μM of VGE significantly enhanced the number of cells in sub-G1 phase. The VGE treatment cleaved pro-caspase-8/-9 and-3 in H1650 and HCC827 cells at 72 h. The VGE treatment of H1650 and HCC827 cells reduced Mcl-1 protein expression. Treatment of H1650 and HCC827 cells with VGE markedly decreased the level of p-Akt. However, dominant-negative caspase-9 (caspase-9 dN) plasmid transfection prevented the viability-inhibitory effect of VGE on H1650 and HCC827 cells. Treatment of H1650 and HCC827 cells with VGE increased levels of cytochrome c in the cytosol. Conclusions VGE inhibited lung carcinoma cell viability by apoptosis activation through a caspase-dependent pathway. Therefore, VGE is a potent anti-cancer agent against lung cancer cells.
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Affiliation(s)
- Bing Han
- Department of Cardio-Thoracic Surgery, People's Hospital of Deyang City, Deyang, Sichuan, China (mainland)
| | - Jianqiang Wu
- Department of Cardio-Thoracic Surgery, People's Hospital of Deyang City, Deyang, Sichuan, China (mainland)
| | - Lei Huang
- Department of Cardio-Thoracic Surgery, People's Hospital of Deyang City, Deyang, Sichuan, China (mainland)
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Lee SY, Kwon J, Woo JH, Kim KH, Lee KA. Bcl2l10 mediates the proliferation, invasion and migration of ovarian cancer cells. Int J Oncol 2019; 56:618-629. [PMID: 31894274 DOI: 10.3892/ijo.2019.4949] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 12/02/2019] [Indexed: 11/05/2022] Open
Abstract
Bcl2l10, also known as Diva, Bcl‑b and Boo, is a member of the Bcl2 family of proteins, which are involved in signaling pathways that regulate cell apoptosis and autophagy. Previously, it was demonstrated that Bcl2l10 plays a crucial role in the completion of oocyte meiosis and is a key regulator of Aurora kinase A (Aurka) expression and activity in oocytes. Aurka is overexpressed in several types of solid tumors and has been considered a target of cancer therapy. Based on these previous results, in the present study, the authors aimed to investigate the regulatory role of Bcl2l10 in A2780 and SKOV3 human ovarian cancer cells. The protein expression of Bcl2l10 was examined in human cancer tissues and cell lines, including the ovaries, using a tissue microarray and various human ovarian cancer cell lines. It was found that Bcl2l10 regulated the protein stability and activities of Aurka in ovarian cancer cells. Although apoptosis was not affected, the cell cycle was arrested at the G0/G1 phase by Bcl2l10 knockdown. Of note, cell viability and motility were markedly increased by Bcl2l10 knockdown. On the whole, the findings of this study suggest that Bcl2l10 functions as tumor suppressor gene in ovarian cancer.
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Affiliation(s)
- Su-Yeon Lee
- Department of Biomedical Sciences, College of Life Sciences, CHA University, Seongnam‑si, Gyeonggi‑do 13488, Republic of Korea
| | - Jinie Kwon
- Department of Biomedical Sciences, College of Life Sciences, CHA University, Seongnam‑si, Gyeonggi‑do 13488, Republic of Korea
| | - Ji Hye Woo
- Department of Biomedical Sciences, College of Life Sciences, CHA University, Seongnam‑si, Gyeonggi‑do 13488, Republic of Korea
| | - Kyeoung-Hwa Kim
- Department of Biomedical Sciences, College of Life Sciences, CHA University, Seongnam‑si, Gyeonggi‑do 13488, Republic of Korea
| | - Kyung-Ah Lee
- Department of Biomedical Sciences, College of Life Sciences, CHA University, Seongnam‑si, Gyeonggi‑do 13488, Republic of Korea
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Aghaei M, KhanAhmad H, Aghaei S, Ali Nilforoushzadeh M, Mohaghegh MA, Hejazi SH. The role of Bax in the apoptosis of Leishmania-infected macrophages. Microb Pathog 2019; 139:103892. [PMID: 31778755 DOI: 10.1016/j.micpath.2019.103892] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 10/30/2019] [Accepted: 11/23/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Leishmania is a protozoan parasite that nests in macrophages and is responsible for the Leishmaniasis disease. In spite of different defense pathways, last strategy of macrophage for killing parasite is apoptosis process. By permeableizing the mitochondrial outer membrane (MOM). As breaching MOM releases apoptogenic factors like cytochrome-c which activate caspases that result in the destruction of the cell. In this review, we summarized the appropriate manuscripts regarding the bax includes, its different types and the effect of bax on the apoptosis of Leishmania and parasite-infected macrophages. METHODS Information about the role of BAX in the apoptosis of parasite-infected macrophage of recent articles were surveyed by searching computerized bibliographic database PubMed and Google Scholar entering the keywords BAX and leishmaniasis. RESULTS The common studies revealed Leishmania use different survival strategies for inhibiting macrophage apoptosis. As Leishmania by preventing homooligomerization or upregulating the anti-apoptotic molecule Bcl-2 can prohibits proteins of host-cell apoptosis such as Bax that is required for mitochondrial permeabilisation during apoptosis. CONCLUSION With regard to the supportive role of bax in apoptosis and the preventive role of Leishmania in its function, it seems that expression of bax gene in parasite by technologies like transgenic or down regulating of anti-apoptotic molecule Bcl-2 by miRNA could be prompted the apoptosis process of infected-macrophages and inhibited extensive spread of Leishmania and the resulting lesions.
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Affiliation(s)
- Maryam Aghaei
- Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein KhanAhmad
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shahrzad Aghaei
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | | | - Mohammad-Ali Mohaghegh
- Department of Laboratory Sciences, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran; Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Seyed Hossein Hejazi
- Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Skin Disease and Leishmaniasis Research Center, Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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Boac BM, Abbasi F, Ismail-Khan R, Xiong Y, Siddique A, Park H, Han M, Saeed-Vafa D, Soliman H, Henry B, Pena MJ, McClung EC, Robertson SE, Todd SL, Lopez A, Sun W, Apuri S, Lancaster JM, Berglund AE, Magliocco AM, Marchion DC. Expression of the BAD pathway is a marker of triple-negative status and poor outcome. Sci Rep 2019; 9:17496. [PMID: 31767884 PMCID: PMC6877530 DOI: 10.1038/s41598-019-53695-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 10/28/2019] [Indexed: 02/01/2023] Open
Abstract
Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment. Therapies enhancing cancer cell sensitivity to cytotoxic agents could significantly improve patient outcomes. A BCL2-associated agonist of cell death (BAD) pathway gene expression signature (BPGES) was derived using principal component analysis (PCA) and evaluated for associations with the TNBC phenotype and clinical outcomes. Immunohistochemistry was used to determine the relative expression levels of phospho-BAD isoforms in tumour samples. Cell survival assays evaluated the effects of BAD pathway inhibition on chemo-sensitivity. BPGES score was associated with TNBC status and overall survival (OS) in breast cancer samples of the Moffitt Total Cancer Care dataset and The Cancer Genome Atlas (TCGA). TNBC tumours were enriched for the expression of phospho-BAD isoforms. Further, the BPGES was associated with TNBC status in breast cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE). Targeted inhibition of kinases known to phosphorylate BAD protein resulted in increased sensitivity to platinum agents in TNBC cell lines compared to non-TNBC cell lines. The BAD pathway is associated with triple-negative status and OS. TNBC tumours were enriched for the expression of phosphorylated BAD protein compared to non-TNBC tumours. These findings suggest that the BAD pathway it is an important determinant of TNBC clinical outcomes.
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Affiliation(s)
- Bernadette M Boac
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
- Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Forough Abbasi
- Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Roohi Ismail-Khan
- Department of Oncologic Sciences, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
- Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Yin Xiong
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
- Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Atif Siddique
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Hannah Park
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
- Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Mingda Han
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
- Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Daryoush Saeed-Vafa
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Hatem Soliman
- Department of Oncologic Sciences, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
- Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Brendon Henry
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - M Juliana Pena
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - E Clair McClung
- University of Arizona Cancer Center, Obstetrics and Gynecology, Tucson, AZ, 85724, USA
| | | | - Sarah L Todd
- Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Alex Lopez
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Weihong Sun
- Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Susmitha Apuri
- Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | | | - Anders E Berglund
- Department of Bioinformatics and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | | | - Douglas C Marchion
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.
- Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.
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Liu Y, Hou J, Zhang M, Seleh-Zo E, Wang J, Cao B, An X. circ-016910 sponges miR-574-5p to regulate cell physiology and milk synthesis via MAPK and PI3K/AKT-mTOR pathways in GMECs. J Cell Physiol 2019; 235:4198-4216. [PMID: 31663119 PMCID: PMC7028128 DOI: 10.1002/jcp.29370] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 10/07/2019] [Indexed: 12/20/2022]
Abstract
Incremental proofs demonstrate that miRNAs, the essential regulators of gene expression, are implicated in various biological procedures, including mammary development and milk synthesis. Here, the role of miR-574-5p in milk synthesis, apoptosis, and proliferation of goat mammary epithelial cells (GMECs) are explored without precedent, and the molecular mechanisms for the impacts are elucidated. Small RNA libraries were constructed using GMECs transfected with miR-574-5p mimics and negative control followed by sequencing via Solexa technology. Overall, 332 genes were distinguishingly expressed entre two libraries, with 74 genes upregulated and 258 genes downregulated. This approach revealed mitogen-activated protein kinase kinase kinase 9 (MAP3K9), an upstream activator of MAPK signaling, as a differentially expressed unigene. miR-574-5p targeted seed sequences of the MAP3K9 3'-untranslated region and suppressed its messenger RNA (mRNA) and protein levels, correspondingly. GMECs with miR-574-5p overexpression and MAP3K9 inhibition showed increased cell apoptosis and decreased cell proliferation resulting from sustained suppression of MAPK pathways, while MAP3K9 elevation manifested the opposite results. miR-574-5p repressed the phosphorylation of members of protein kinase B (AKT)-mammalian target of rapamycin pathway via downregulating MAP3K9 and AKT3, resulting in reducing the secretion of β-casein and triglycerides in GMECs. Finally, according to the constructed circular RNA (circRNA) libraries and bioinformatics prediction approach, we selected circ-016910 and found it acted as a sponge for miR-574-5p and blocked its relevant behaviors to undertake biological effects in GMECs. The circRNA-miRNA-mRNA network facilitates further probes on the function of miR-574-5p in mammary development and milk synthesis.
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Affiliation(s)
- Yuhan Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Jinxing Hou
- Animal Engineering Branch, Yangling Vocational and Technical College, Yangling, Shaanxi, China
| | - Meng Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Emeline Seleh-Zo
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Jiangang Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Binyun Cao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Xiaopeng An
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
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Wu Y, Wang Y, Liu Q, Zhu LJ, Gao H, Cui M, Liu J, Zhao P, Liu J, Chen L, Wang J, Zeng W, Woodruff TK, Zeng S. Conserved microRNA mediates heating tolerance in germ cells versus surrounding somatic cells. RNA Biol 2019; 16:1494-1503. [PMID: 31276432 DOI: 10.1080/15476286.2019.1639311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Mammalian fertility is reduced during heat exposure in the summer, but is regained as temperatures decrease in the autumn again. However, the mechanism underlying the phenomenon remains unknown. We investigated heat stress tolerance of germ cells and their surrounding somatic cells, and discovered that microRNA ssc-ca-1 was upregulated after heat stress in cultured porcine granulosa cells (GCs), but not in serum-starved GCs. Ssc-ca-1 inhibited heat shock protein 70 (Hsp70) expression through its 3'- and 5'-UTRs. Although Hsp70 mRNA transcription was induced in GCs by in vivo exposure to heat in the summer, ssc-ca-1 inhibited Hsp70 expression. In ovarian cultures, heat stress-induced Hsp70 expression in primordial but not in growing follicles; ssc-ca-1 expression did not change in primordial follicles, but increased in growing follicles. Consistently, ssc-ca-1 was present in testicular cells and exhibited the same function as in ovarian cells. It modulated the different Hsp70 expression between spermatogonial stem cells and Sertoli cells after scrotal heat stress. This mechanism is of relevance to mammalian fertility in parts of the world dominated by heat stress associated with global climate change.
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Affiliation(s)
- Yi Wu
- National Engineering Laboratory for Animal Breeding; Key Laboratory of Animal Genetics, Breeding, and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University , Beijing , China.,School of Basic Medical Science, Capital Medical University , Beijing , China.,Laboratory Animal Center, Capital Medical University , Beijing , China
| | - Yingzheng Wang
- National Engineering Laboratory for Animal Breeding; Key Laboratory of Animal Genetics, Breeding, and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University , Beijing , China
| | - Qiang Liu
- National Engineering Laboratory for Animal Breeding; Key Laboratory of Animal Genetics, Breeding, and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University , Beijing , China
| | - Lihua Julie Zhu
- Molecular, Cell and Cancer Biology, Program in Molecular Medicine, Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School , Worcester , MA , USA
| | - Hui Gao
- National Engineering Laboratory for Animal Breeding; Key Laboratory of Animal Genetics, Breeding, and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University , Beijing , China
| | - Maosheng Cui
- Biotechnology Laboratory of Animal Reproduction, Tianjin Academy of Animal Science , Tianjin , China
| | - Jinghao Liu
- Laboratory Animal Center, Peking University , Beijing , China
| | - Pengju Zhao
- National Engineering Laboratory for Animal Breeding; Key Laboratory of Animal Genetics, Breeding, and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University , Beijing , China
| | - Jianfeng Liu
- National Engineering Laboratory for Animal Breeding; Key Laboratory of Animal Genetics, Breeding, and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University , Beijing , China
| | - Lei Chen
- Key Laboratory of Pig Industry Sciences (Ministry of Agriculture), Chongqing Academy of Animal Science , Chongqing , China
| | - Jinyong Wang
- Key Laboratory of Pig Industry Sciences (Ministry of Agriculture), Chongqing Academy of Animal Science , Chongqing , China
| | - Wenxian Zeng
- College of Animal Science and Technology, Northwest A&F University , Shaanxi , China
| | - Teresa K Woodruff
- Division of Fertility Preservation, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University , Chicago , IL , USA
| | - Shenming Zeng
- National Engineering Laboratory for Animal Breeding; Key Laboratory of Animal Genetics, Breeding, and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University , Beijing , China
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Keyvanloo Shahrestanaki M, Bagheri M, Ghanadian M, Aghaei M, Jafari SM. Centaurea cyanus
extracted 13‐O‐acetylsolstitialin A decrease Bax/Bcl‐2 ratio and expression of cyclin D1/Cdk‐4 to induce apoptosis and cell cycle arrest in MCF‐7 and MDA‐MB‐231 breast cancer cell lines. J Cell Biochem 2019; 120:18309-18319. [DOI: 10.1002/jcb.29141] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 12/13/2018] [Accepted: 01/10/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Mohammad Keyvanloo Shahrestanaki
- Department of Clinical Biochemistry, School of Pharmacy & Pharmaceutical Sciences Isfahan University of Medical Sciences Isfahan I.R. Iran
| | - Mahboobeh Bagheri
- Department of Clinical Biochemistry, School of Pharmacy & Pharmaceutical Sciences Isfahan University of Medical Sciences Isfahan I.R. Iran
| | - Mustafa Ghanadian
- Department of Pharmacognosy Isfahan University of Medical Sciences Isfahan I.R. Iran
- National Center for Natural Products Research, School of Pharmacy Mississippi University Oxford Mississippi
| | - Mahmoud Aghaei
- Department of Clinical Biochemistry, School of Pharmacy & Pharmaceutical Sciences Isfahan University of Medical Sciences Isfahan I.R. Iran
| | - Seyyed Mehdi Jafari
- Metabolic Disorders Research Center Golestan University of Medical Sciences Gorgan I.R. Iran
- Department of Biochemistry and Biophysics, Faculty of Medicine Golestan University of Medical Sciences Gorgan I.R. Iran
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41
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Sharma R, Battu P, Singla M, Goyal N, Sharma VL. Expression profile of markers of oxidative stress, injury and apoptosis in anti-tuberculosis drugs induced nephrotoxicity. Nephrology (Carlton) 2019; 24:689-695. [PMID: 29737591 DOI: 10.1111/nep.13399] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/02/2018] [Indexed: 12/28/2022]
Abstract
AIM Isoniazid (INH), Rifampicin (RIF) and Pyrazinamide (PZA) are part of first-line anti-tuberculosis therapy used against infection caused by Mycobacterium tuberculosis. However, these drugs are known to be potentially harmful as these are associated with numerous side effects and when taken together their harmful outcomes are elevated in a synergistic manner. Identification of possible mechanism underlying RIF + INH + PZA induced nephrotoxicity may be advantageous in developing strategies to prevent their toxic implications. METHODS In this study rats were distributed in two groups of six each: Control (tap water) and Toxicant (INH + RIF + PZA) in dosage derived through extrapolation from human dosage for 28 days once in a day. Antioxidant activity and histology of kidney were examined. In addition, apoptosis was also studied using pro and anti-apoptotic markers and TUNEL staining to check nephrotoxicity. RESULTS Findings indicated that combined (INH, RIF and PZA) 28 day exposure in Wistar rats caused increase in number of free radicals/ reactive oxygen species which further cause changes in levels of enzymatic antioxidants such as glutathione, Superoxide dismutase, Catalase, and Glutathione-s-transferase. Altered content of pro (BAD&BAX) and anti-apoptotic genes (BCL-2&BCL2L1) genes, TUNEL positive cells and DNA fragmentation emphasized involvement of apoptosis. CONCLUSION This study concluded that nephrotoxicity is accompanied during combinational anti-tuberculosis drug therapy.
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Affiliation(s)
- Radhika Sharma
- Cytogenetics Laboratory, Department of Zoology, Panjab University, Chandigarh, India.,Department of Zoology, School of Basic and Applied Sciences, Maharaja Agrasen University, Baddi, India
| | - Priya Battu
- Cytogenetics Laboratory, Department of Zoology, Panjab University, Chandigarh, India
| | - Mandakini Singla
- Cytogenetics Laboratory, Department of Zoology, Panjab University, Chandigarh, India
| | - Neha Goyal
- Cytogenetics Laboratory, Department of Zoology, Panjab University, Chandigarh, India
| | - Vijay L Sharma
- Cytogenetics Laboratory, Department of Zoology, Panjab University, Chandigarh, India
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Santos LC, Vogel R, Chipuk JE, Birtwistle MR, Stolovitzky G, Meyer P. Mitochondrial origins of fractional control in regulated cell death. Nat Commun 2019; 10:1313. [PMID: 30899020 PMCID: PMC6428895 DOI: 10.1038/s41467-019-09275-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 03/01/2019] [Indexed: 11/09/2022] Open
Abstract
Individual cells in clonal populations often respond differently to environmental changes; for binary phenotypes, such as cell death, this can be measured as a fractional response. These types of responses have been attributed to cell-intrinsic stochastic processes and variable abundances of biochemical constituents, such as proteins, but the influence of organelles is still under investigation. We use the response to TNF-related apoptosis inducing ligand (TRAIL) and a new statistical framework for determining parameter influence on cell-to-cell variability through the inference of variance explained, DEPICTIVE, to demonstrate that variable mitochondria abundance correlates with cell survival and determines the fractional cell death response. By quantitative data analysis and modeling we attribute this effect to variable effective concentrations at the mitochondria surface of the pro-apoptotic proteins Bax/Bak. Further, our study suggests that inhibitors of anti-apoptotic Bcl-2 family proteins, used in cancer treatment, may increase the diversity of cellular responses, enhancing resistance to treatment. Phenotypic cell-to-cell variability contributes to fractional killing, but the mechanisms are incompletely understood. Here the authors show that mitochondrial density correlates with cell survival in response to TRAIL, and that variable effective concentrations of Bax/Bak contribute to the effect.
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Affiliation(s)
- Luís C Santos
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Robert Vogel
- IBM T.J. Watson Research Center, 1101 Kitchawan Road, Yorktown Heights, NY, 10598, USA.,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jerry E Chipuk
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA
| | - Marc R Birtwistle
- Systems Biology Center New York, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. .,Department of Chemical and Biomolecular Engineering, Clemson University, Clemson, SC, 29634, USA.
| | - Gustavo Stolovitzky
- IBM T.J. Watson Research Center, 1101 Kitchawan Road, Yorktown Heights, NY, 10598, USA. .,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Pablo Meyer
- IBM T.J. Watson Research Center, 1101 Kitchawan Road, Yorktown Heights, NY, 10598, USA. .,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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Knight T, Luedtke D, Edwards H, Taub JW, Ge Y. A delicate balance - The BCL-2 family and its role in apoptosis, oncogenesis, and cancer therapeutics. Biochem Pharmacol 2019; 162:250-261. [PMID: 30668936 DOI: 10.1016/j.bcp.2019.01.015] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 01/18/2019] [Indexed: 01/06/2023]
Abstract
Evasion of apoptosis is fundamental to the pathogenesis of cancer. Members of the B-cell Lymphoma 2 (BCL-2) protein family are key pro- and anti-apoptotic regulators, and in healthy cells are held in a fine, delicate balance - perturbations of which may tip a cell irreversibly towards cellular death or, conversely, allow a cell to permanently escape apoptosis and immortalize itself as a malignant clone. The restoration of this balance or, indeed, adjustment in favor of apoptosis via manipulation of the BCL-2 family, is a promising area in the realm of molecular therapeutics, and one in which breathtaking advances are currently being made. The purpose of this review is to outline the role of the BCL-2 family in apoptosis, to contrast its optimal functioning with those disruptions seen in malignancy, and to provide an overview of the medications both presently available and currently under development which selectively target members of this family.
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Affiliation(s)
- Tristan Knight
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI, USA; Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Daniel Luedtke
- Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI, USA
| | - Holly Edwards
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | - Jeffrey W Taub
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI, USA; Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | - Yubin Ge
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI, USA; Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
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Adams CM, Clark-Garvey S, Porcu P, Eischen CM. Targeting the Bcl-2 Family in B Cell Lymphoma. Front Oncol 2019; 8:636. [PMID: 30671383 PMCID: PMC6331425 DOI: 10.3389/fonc.2018.00636] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 12/05/2018] [Indexed: 12/21/2022] Open
Abstract
Although lymphoma is a very heterogeneous group of biologically complex malignancies, tumor cells across all B cell lymphoma subtypes share a set of underlying traits that promote the development and sustain malignant B cells. One of these traits, the ability to evade apoptosis, is essential for lymphoma development. Alterations in the Bcl-2 family of proteins, the key regulators of apoptosis, is a hallmark of B cell lymphoma. Significant efforts have been made over the last 30 years to advance knowledge of the biology, molecular mechanisms, and therapeutic potential of targeting Bcl-2 family members. In this review, we will highlight the complexities of the Bcl-2 family, including our recent discovery of overexpression of the anti-apoptotic Bcl-2 family member Bcl-w in lymphomas, and describe recent advances in the field that include the development of inhibitors of anti-apoptotic Bcl-2 family members for the treatment of B cell lymphomas and their performance in clinical trials.
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Affiliation(s)
- Clare M Adams
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Sean Clark-Garvey
- Internal Medicine Residency Program, Department of Internal Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
| | - Pierluigi Porcu
- Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Christine M Eischen
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
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Abstract
BCL-2 family proteins interact in a network that regulates apoptosis. The BH3 amino acid sequence motif serves to bind together this conglomerate protein family, both literally and figuratively. BH3 motifs are present in antiapoptotic and proapoptotic BCL-2 homologs, and in a separate group of unrelated BH3-only proteins often appended to the BCL-2 family. BH3-containing helices mediate many of their physical interactions to determine cell death versus survival, leading to the development of BH3 mimetics as therapeutics. Here we provide an overview of BCL-2 family interactions, their relevance in health and disease, and the progress toward regulating their interactions therapeutically.
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Affiliation(s)
- Jason D Huska
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Heather M Lamb
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - J Marie Hardwick
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
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Bcl-2 Family Overexpression and Chemoresistance in Acute Myeloid Leukemia. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2018. [DOI: 10.2478/sjecr-2018-0064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
The family of Bcl-2 proteins is one of the most responsible for apoptosis pathway, that is a critical process to the maintenance of tissue homeostasis. Bcl-2 is an essential apoptotic regulator belonging to a family of functionally and structurally related proteins known as the Bcl-2 family. Some members of this family act as anti-apoptotic regulators, whereas others act in pro-apoptotic function. The relationship between the pro and anti-apoptotic proteins can regulate whether cells begin the apoptosis or remain its life cycle. Increasing of Bcl-2 expression has been found in some hematologic diseases, such as Acute Myeloid Leukemia (AML) and their effects on responsiveness to anticancer therapy have been recently described. Thus, this review aims to discuss apoptosis and the role of the Bcl-2 family of proteins in chemoresistance when overexpressed in patients committed with Acute Myeloid Leukemia submitted to chemotherapy treatment.
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Choi E, Yoo W, Park JH, Kim S. Simultaneous Delivery of Electrostatically Complexed Multiple Gene-Targeting siRNAs and an Anticancer Drug for Synergistically Enhanced Treatment of Prostate Cancer. Mol Pharm 2018; 15:3777-3785. [PMID: 30028622 DOI: 10.1021/acs.molpharmaceut.8b00227] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Simultaneous silencing of multiple apoptosis-related genes is an attractive approach to treat cancer. In this article, we present a multiple gene-targeting siRNA/drug delivery system for prostate cancer treatment with a high efficiency. Bcl-2, survivin, and androgen receptor genes involved in the cell apoptosis pathways were chosen as silencing targets with three different siRNAs. The colloidal nanocomplex delivery system (<10 nm in size) was formulated electrostatically between anionic siRNAs and a cationic drug (BZT), followed by encapsulation with the Pluronic F-68 polymer. The formulated nanocomplex system exhibited sufficient stability against nuclease-induced degradation, leading to successful intracellular delivery for the desired therapeutic performance. Silencing of targeted genes and apoptosis induction were evaluated in vitro on human prostate LNCaP-LN3 cancer cells by using various biological analysis tools (e.g., real-time PCR, MTT cell viability test, and flow cytometry). It was demonstrated that when the total loaded siRNA amounts were kept the same in the nanocomplexes, the simultaneous silencing of triple genes with co-loaded siRNAs (i.e., Bcl-2, survivin, and AR-targeting siRNAs) enhanced BZT-induced apoptosis of cancer cells more efficiently than the silencing of each single gene alone, offering a novel way of improving the efficacy of gene therapeutics including anticancer drug.
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Affiliation(s)
- Eunshil Choi
- Center for Theragnosis , Korea Institute of Science and Technology (KIST) , Seoul 136-791 , Korea
| | - Wonjae Yoo
- Center for Theragnosis , Korea Institute of Science and Technology (KIST) , Seoul 136-791 , Korea.,School of Chemical Engineering, College of Engineering , Sungkyunkwan Univeristy , Suwon 440-746 , Korea
| | - Jae Hyung Park
- School of Chemical Engineering, College of Engineering , Sungkyunkwan Univeristy , Suwon 440-746 , Korea
| | - Sehoon Kim
- Center for Theragnosis , Korea Institute of Science and Technology (KIST) , Seoul 136-791 , Korea.,Division of Bio-Medical Science & Technology, KIST School , Korea University of Science and Technology (UST) , Seoul 136-791 , Korea
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48
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Needell JC, Brown MN, Zipris D. Involvement of adipose tissue inflammation and dysfunction in virus-induced type 1 diabetes. J Endocrinol 2018; 238:61-75. [PMID: 29743341 DOI: 10.1530/joe-18-0131] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 05/08/2018] [Indexed: 12/16/2022]
Abstract
The etiopathogenesis of type 1 diabetes (T1D) remains poorly understood. We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced T1D to better understand the role of the innate immune system in the mechanism of virus-induced disease. We observed that infection with KRV results in cell influx into visceral adipose tissue soon following infection prior to insulitis and hyperglycemia. In sharp contrast, subcutaneous adipose tissue is free of cellular infiltration, whereas β cell inflammation and diabetes are observed beginning on day 14 post infection. Immunofluorescence studies further demonstrate that KRV triggers CD68+ macrophage recruitment and the expression of KRV transcripts and proinflammatory cytokines and chemokines in visceral adipose tissue. Adipocytes from naive rats cultured in the presence of KRV express virus transcripts and upregulate cytokine and chemokine gene expression. KRV induces apoptosis in visceral adipose tissue in vivo, which is reflected by positive TUNEL staining and the expression of cleaved caspase-3. Moreover, KRV leads to an oxidative stress response and downregulates the expression of adipokines and genes associated with mediating insulin signaling. Activation of innate immunity with Poly I:C in the absence of KRV leads to CD68+ macrophage recruitment to visceral adipose tissue and a decrease in adipokine expression detected 5 days following Poly (I:C) treatment. Finally, proof-of-principle studies show that brief anti-inflammatory steroid therapy suppresses visceral adipose tissue inflammation and protects from virus-induced disease. Our studies provide evidence raising the hypothesis that visceral adipose tissue inflammation and dysfunction may be involved in early mechanisms triggering β cell autoimmunity.
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Affiliation(s)
- James C Needell
- Barbara Davis Center for Childhood DiabetesUniversity of Colorado Denver, Aurora, Colorado, USA
| | - Madalyn N Brown
- Barbara Davis Center for Childhood DiabetesUniversity of Colorado Denver, Aurora, Colorado, USA
| | - Danny Zipris
- Barbara Davis Center for Childhood DiabetesUniversity of Colorado Denver, Aurora, Colorado, USA
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Ong YS, Saiful Yazan L, Ng WK, Abdullah R, Mustapha NM, Sapuan S, Foo JB, Tor YS, How CW, Abd Rahman N, Zakarial Ansar FH. Thymoquinone loaded in nanostructured lipid carrier showed enhanced anticancer activity in 4T1 tumor-bearing mice. Nanomedicine (Lond) 2018; 13:1567-1582. [DOI: 10.2217/nnm-2017-0322] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Aim: To investigate the enhancement of anticancer activity of thymoquinone (TQ) by the use of nanostructured lipid carrier (NLC) in 4T1 tumor-bearing female BALB/c mice. Material & methods: TQ was incorporated into NLC (TQNLC) by using high pressure homogenization. TQNLC and TQ were orally administered to the mice. Results & conclusion: TQNLC and TQ are potential chemotherapeutic drugs as they exhibited anticancer activity. The use of NLC as a carrier has enhanced the therapeutic property of TQ by increasing the survival rate of mice. The antimetastasis effect of TQNLC and TQ to the lungs was evidence by downregulation of MMP-2. TQNLC and TQ induced apoptosis via modulation of Bcl-2 and caspase-8 in the intrinsic apoptotic pathway.
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Affiliation(s)
- Yong Sze Ong
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Latifah Saiful Yazan
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
- Department of Biomedical Science, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Wei Keat Ng
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Rasedee Abdullah
- Department of Pathology & Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM Serdang, Malaysia
| | - Noordin M Mustapha
- Department of Pathology & Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM Serdang, Malaysia
| | - Sarah Sapuan
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Jhi Biau Foo
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Yin Sim Tor
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Chee Wun How
- Department of Pathology & Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM Serdang, Malaysia
| | - Napsiah Abd Rahman
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Fatin Hannani Zakarial Ansar
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
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50
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Girnius N, Davis RJ. JNK Promotes Epithelial Cell Anoikis by Transcriptional and Post-translational Regulation of BH3-Only Proteins. Cell Rep 2018; 21:1910-1921. [PMID: 29141222 DOI: 10.1016/j.celrep.2017.10.067] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 09/27/2017] [Accepted: 10/18/2017] [Indexed: 11/18/2022] Open
Abstract
Developmental morphogenesis, tissue injury, and oncogenic transformation can cause the detachment of epithelial cells. These cells are eliminated by a specialized form of apoptosis (anoikis). While the processes that contribute to this form of cell death have been studied, the underlying mechanisms remain unclear. Here, we tested the role of the cJUN NH2-terminal kinase (JNK) signaling pathway using murine models with compound JNK deficiency in mammary and kidney epithelial cells. These studies demonstrated that JNK is required for efficient anoikis in vitro and in vivo. Moreover, JNK-promoted anoikis required pro-apoptotic members of the BCL2 family of proteins. We show that JNK acts through a BAK/BAX-dependent apoptotic pathway by increasing BIM expression and phosphorylating BMF, leading to death of detached epithelial cells.
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Affiliation(s)
- Nomeda Girnius
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Roger J Davis
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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