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The Role of Mitochondrial Dysfunction in Mitophagy and Apoptosis and Its Relevance to Cancer
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
In addition to direct MOMP effectors, another class of pro-apoptotic factors is comprised of proteins, that harbor only one BH domain (BH3) in their primary sequence, known as the BH3-only protein sub-family [60]. BH3-only proteins such as Bcl-2-associated death promoter (Bad), Bcl-2 interacting killer (Bik), Bcl-2 modifying factor (Bmf), harakiri (Hrk), and Noxa sensitize cells to apoptosis by sequestering the pro-survival proteins from interaction with Bax or Bak. Hence, BH3-only proteins are in general referred to as apoptotic sensitizers. In addition, a sub-group of so-called direct activators has been identified among the BH3-only proteins. Apart from acting as sensitizers, proteins such as truncated BH3-interacting domain death agonist (tBid), Bcl-2-like protein 11 (Bim), p53 upregulated modulator of apoptosis (Puma), and Noxa, can directly bind to and activate the MOMP effectors Bax and Bak.
Tumor Biology
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Apoptosis can be initiated either through a “cell extrinsic pathway” or through a “cell intrinsic pathway.” The cell extrinsic pathway involves the death receptors in the cell membrane. Fas receptor when bound to Fas ligand, or TNFa receptor when bound to its TNFα ligand, can initiate the cell extrinsic pathway of apoptosis. Whole hosts of integrin receptors present at the basal surface of epithelial cells are attached to the basement membrane underneath and can induce apoptosis when they are not bound to their ligand. These phenomena in epithelial cells are called “anoikis”—detachment-induced cell death. The cell intrinsic pathway involves the mitochondrial apoptotic pathway initiated by a DNA damage signal from the nucleus. Exposure to chemical genotoxins or radiation results in the blockage of DNA replication, which leads to collapse of replication forks and DNA double strand breaks (DSB) formation. These DSBs are thought to be crucial downstream apoptosis–triggering lesions. DSBs are detected by ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia- and Rad3-related (ATR) proteins, which signal downstream to CHK1, CHK2 (checkpoint kinases), and p53. p53 induces transcriptional activation of proapoptotic factors such as FAS, p53 upregulated modulator of apoptosis (PUMA), and BCL-2 associated X protein (BAX). Many tumors harbor mutations in p53. There are p53 backup systems that involve CHK1- and/or CHK2-driven E2F1 activation and p73 upregulation, which in turn transcribes BAX, PUMA, and NOXA. The end point of the mitochondrial pathway of apoptosis is release of cytochrome C.
Herpesvirus microRNAs for Use in Gene Therapy Immune-Evasion Strategies
Published in Yashwant Pathak, Gene Delivery, 2022
Vineet Mahajan, Shruti Saptarshi, Yashwant Pathak
EBV genome encodes several miRNAs, most of which have been implicated in oncogenesis.23 This may be due to the large array of pro-apoptotic proteins or host tumor suppressor genes targeted by EBV miRNAs. A prominent cellular target of EBV miRNAs is the pro-apoptotic protein PUMA (p53-upregulated modulator of apoptosis), which is regulated by miR-BART5-5p.24 Zheng and colleagues demonstrated that EBV miRNA miR-BART5-3p can inhibit the expression of the critical tumor suppressor gene p53 by directly targeting its 3′-UTR, contributing to tumorigenesis.25 The pro-apoptotic protein TOMM22 (translocase of outer mitochondrial membrane 22 homolog), part of the mitochondrial pore receptor complex for the pro-apoptotic protein BAX (BCL2-associated X protein), was identified as a potential target for ebv-miR-BART16. So are the BCL2-associated death promoter (BAD) protein, another target of the ebv-miR-BART20-5p, and the pro-apoptotic protein caspase 3 identified as being a target of ebv-miR-BART16 and ebv-miR-BART1-3p. Transport of EBV miRNAs from tumors into the blood stream has been implicated in the progression of EBV associated malignancies. This was demonstrated when EBV BART miRNAs were detected as extracellular vesicles secreted by LCLs and nasopharyngeal carcinoma (NPC) cells. BART1-5p, BART5, BART7-3p, BART12, and BART13 were also found in the circulating extracellular vesicles from NPC patients. Clinically, EBV miRNAs my prove to be promising biomarkers for detection of EBV related malignancies. EBV miR-BART3, miR-BART7, and miR-BART13 were highly expressed in EBV-positive NPC. A total of 12 BART miRNAs (miR-BART1-3p, 2-5p, 5, 6-3p, 6-5p, 7, 8, 9, 14, 17-5p, 18-5p, and 19-3p) were validated to be upregulated in NPC tissues versus their non-tumorous biopsies.26 A negative regulatory role several BART-2 miRNAs was demonstrated for the DNA repair gene BRCA1 expression, which also increased the cell sensitivity to DNA damaging chemotherapeutic drugs, cisplatin and doxorubicin, thus facilitating novel NPC therapies.27
The prognostic and clinical value of p53 upregulated modulator of apoptosis expression in solid tumors: a meta-analysis and TCGA data review
Published in Expert Review of Molecular Diagnostics, 2022
Weifeng Gao, Zhen Yuan, Xuanzhu Zhao, Shuyuan Wang, Sizhen Lai, Kemin Ni, Yixiang Zhan, Zhaoce Liu, Lina Liu, Ran Xin, Xin Yin, Xingyu Zhou, Xinyu Liu, Xipeng Zhang, Qinghuai Zhang, Guoxun Li, Wenhong Wang, Chunze Zhang
One of the characteristics of tumors refers to evasion of apoptosis [4]. p53 upregulated modulator of apoptosis (PUMA, also known as BBC3) is a member of the Bcl-2 family and serves as an apoptosis inducer in a variety of tumors, which may decrease tumor growth [5]. It was reported that PUMA plays a critical role in apoptotic signaling pathways and tumorigenesis [6]. PUMA is localized in the mitochondria and induced by a wide range of signals, such as abnormal expression of oncogenes, genotoxic stress and infection [7]. PUMA expression can cause p53-dependent apoptosis [8], which induces cytochrome c release and caspase activation by binding to Bcl-2-related proteins [9]. Overexpression of PUMA can accelerate apoptosis in different tumor cells [10].
LncRNAGAS5 sponges miRNA-221 to promote neurons apoptosis by up-regulated PUMA under hypoxia condition
Published in Neurological Research, 2020
Xiao-Bing Zhou, Ling-Feng Lai, Guang-Bin Xie, Cong Ding, Xiang Xu, Yang Wang
p53-upregulated modulator of apoptosis (PUMA), a member of the Bcl-2 protein family, is required for apoptosis [23]. It has been involved in the onset and progress of cancer [24], acquired immunodeficiency syndrome [25], and ischemic brain disease [23]. Even though the quantitative relationships between GAS5 and some members of the Bcl-2 family were characterized, the influence of GAS5 on PUMA remains elusive.
Molecular Mechanism of Curcumin and Its Analogs as Multifunctional Compounds against Pancreatic Cancer
Published in Nutrition and Cancer, 2022
Qun Huang, Ya Zhang, Yanlin Zheng, Hongjing Yang, Yang Yang, Ya Mo, Liuying Li, Hong Zhang
CDF (3,4-difluoro-benzo-curcumin) is a difluoro analog of curcumin, which is the most widely studied curcumin analog. The analog CDF exhibits greater bioavailability than curcumin in pancreatic tissue (68, 69). Padhye et al. revealed that CDF had better retention and bioavailability in the pancreatic tissue, and the concentration of CDF was 10-fold higher than that of curcumin. They also found that CDF inhibited the growth of PC by reducing the expression of NF-κB and PGE2 levels (68). CDF is a multi-targeted agent that activates c-Myc, p73, and its downstream pro-apoptotic protein Bax, while simultaneously downregulating Bcl-2 to promote apoptosis in PC cells (70). In addition, CDF can re-express miRNAs such as let-7a, b, c, d, miR-26a, miR-101, miR-146a, and miR-200b, that are lost in the PC cell lines, by attenuating histone methyltransferase(EZH2) (71).miR-221 is an oncogenic miRNA (72, 73). Sarkar et al. (74) found significantly upregulated expression of miR-221 in PC cell lines and tumor tissues compared to that in normal pancreatic duct epithelial cells and normal pancreatic tissues. PTEN, p27kip1, p57kip2, and PUMA are miR-221 targets, and PTEN is an important molecule involved in the regulation of cell growth and apoptosis (75). p27kip1 regulates cell proliferation, motility, and apoptosis (76) while p57kip2 controls the cell cycle, cytoskeletal organization, cell migration, and differentiation (77). The p53 upregulated modulator of apoptosis (PUMA) plays a critical role in the regulation of p53-dependent and -independent apoptosis (78). CDF downregulates the expression of miR-221 and consequently upregulates the expression of PTEN, p27kip1, p57kip2, and PUMA, leading to the inhibition of cell proliferation and migration in PC cell lines, suppressing the aggressiveness of PC (74). CDF can also inhibit the expression of VEGF and IL-6 (79), thereby exerting an anti-pancreatic cancer effect. The above results demonstrate that CDF can be a candidate for PC therapy because of its high bioavailability and ability to inhibit the growth of PC through a multi-mechanism inhibitory effect involving the regulation of transcription factors and related proteins, microRNAs, and growth factors.