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Mst1 regulates colorectal cancer stress response via inhibiting bnip3-related mitophagy by activation of JNK/p53 pathway

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CELL BIOLOGY AND TOXICOLOGY 2018年第4期34卷 263-277页

作者： Li, Qi Qi, Feng Meng, Xiangchao Zhu, Chenpei Gao, Yingtang Tianjin Med Univ Dept Gen Surg Cent Clin Coll 3 Tianjin 300170 Peoples R China Tianjin Med Univ Gen Hosp Dept Gen Surg Tianjin 300052 Peoples R China Tianjin Third Cent Hosp Tianjin Key Lab Artificial Cell 83 Jintang Rd Tianjin 300170 Peoples R China

The Hippo-Mst1 pathway is associated with tumor development and progression. However, little evidence is available for its role in colorectal cancer (CRC) stress response via mitochondrial homeostasis. In this study, we conducted gain-of function assay about Mst1 in CRC via adenovirus transfection. Then, cellular viability and apoptosis were measured via MTT, TUNEL assay, and typan blue staining. Mitochondrial function was detected via JC1 staining, mPTP opening assay, and immunofluorescence of cyt-c. Mitophagy was observed via western blots and immunofluorescence. Cell migration and proliferation were evaluated via Transwell and BrdU assay. Western blots were used to analyze the signaling pathways with JNK inhibitors or p53 siRNA. We found that Mst1 was down-regulated in CRC. Overexpression of Mst1 induced CRC apoptosis and impaired cell proliferation and migration. Functional studies have illustrated that recovery of Mst1 could activate JNK pathway which upregulated the p53 expression. The latter repressed bnip3 transcription and activity, leading to the mitophagy arrest. The defective mitophagy impaired mitochondrial homeostasis, evoked cellular oxidative stress, and initiated the mitochondrial apoptosis. Meanwhile, bad-structured mitophagy also hindered the cancer proliferation via CyclinD/E. Moreover, Mst1-suppressed mitophagy was associated with CRC migration inhibition via regulation of CXCR4/7 expression. Collectively, our data described the comprehensive role of Mst1 in colorectal cancer stress response involving apoptosis, mobilization, and growth via handling mitophagy by JNK/p53/bnip3 pathways.

关键词： Mst1 Colorectal cancer Mitophagy p53 bnip3

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FOXO3a regulates bnip3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress

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AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 2016年第6期311卷 H1540-H1559页

作者： Chaanine, Antoine H. Kohlbrenner, Erik Gamb, Scott I. Guenzel, Adam J. Klaus, Katherine Fayyaz, Ahmed U. Nair, K. Sreekumaran Hajjar, Roger J. Redfield, Margaret M. Mayo Clin Div Cardiovasc Dis 200 First St SW Rochester MN 55905 USA Mt Sinai Sch Med Div Cardiovasc Dis New York NY USA Mayo Clin Dept Biochem & Cell Biol Microscopy & Cell Anal Core 200 First St SW Rochester MN 55905 USA Mayo Clin Div Endocrinol 200 First St SW Rochester MN 55905 USA

The forkhead box O3a (FOXO3a) transcription factor has been shown to regulate glucose metabolism, muscle atrophy, and cell death in postmitotic cells. Its role in regulation of mitochondrial and myocardial function is not well studied. Based on previous work, we hypothesized that FOXO3a, through BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (bnip3), modulates mitochondrial morphology and function in heart failure (HF). We modulated the FOXO3a-bnip3 pathway in normal and phenylephrine (PE)-stressed adult cardiomyocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative FOXO3a (AAV9. dn-FX3a) for gene delivery in a rat model of HF with preserved ejection fraction (HFpEF). We found that FOXO3a upregulates bnip3 expression in normal and PE-stressed ACM, with subsequent increases in mitochondrial Ca2+, leading to decreased mitochondrial membrane potential, mitochondrial fragmentation, and apoptosis. Whereas dn-FX3a attenuated the increase in bnip3 expression and its consequences in PE-stressed ACM, AAV9. dn-FX3a delivery in an experimental model of HFpEF decreased bnip3 expression, reversed adverse left ventricular remodeling, and improved left ventricular systolic and, particularly, diastolic function, with improvements in mitochondrial structure and function. Moreover, AAV9. dnFX3a restored phospholamban phosphorylation at S16 and enhanced dynamin-related protein 1 phosphorylation at S637. Furthermore, FOXO3a upregulates maladaptive genes involved in mitochondrial apoptosis, autophagy, and cardiac atrophy. We conclude that FOXO3a activation in cardiac stress is maladaptive, in that it modulates Ca2+ cycling, Ca2+ homeostasis, and mitochondrial dynamics and function. Our results suggest an important role of FOXO3a in HF, making it an attractive potential therapeutic target.

关键词： heart failure calcium regulation apoptosis FOXO3a bnip3

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Localization and developmental ontogeny of the pro-apoptotic bnip3 mRNA in the postnatal rat cortex and hippocampus

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BRAIN RESEARCH 2006年第1期1100卷 55-63页

作者： Sandau, Ursula S. Handa, Robert J. Colorado State Univ Dept Biomed Sci Ft Collins CO 80523 USA

Naturally occurring cell death occurs during the first two postnatal weeks in the rat cortex and hippocampus. During this process, apoptosis is initiated by activating or altering expression of pro-apoptotic members of the Bcl-2 family. bnip3 is a pro-apoptotic member of the Bcl-2 family that induces cell death by opening the mitochondrial permeability transition pore. To date, bnip3 expression in the central nervous system has only been examined during hypoxia-mediated apoptosis in the adult rat brain. In this study, we investigated the localization and ontogeny of bnip3 mRNA expression in the postnatal male and female rat brain. bnip3 mRNA was localized by in situ hybridization in the neonatal cortex, hippocampus, habenula and thalamus. Using quantitative real-time RT-PCR, bnip3 mRNA levels were found to be greatest at postnatal day 6.5 in the female anterior and posterior cingulate cortices and hippocampus. bnip3 mRNA expression also increased in the male anterior cingulate cortex at postnatal day 6.5. However, a developmental change in bnip3 levels did not occur in the male posterior cingulate cortex and hippocampus. In the anterior cingulate cortex on postnatal day 6.0 and adulthood, female rats had significantly greater levels of bnip3 mRNA compared to that of males. Altering levels of testosterone in the neonatal rat did not alter the sex differences in bnip3 mRNA levels. The transient increase in bnip3 mRNA expression correlates with naturally occurring cell death in the neonatal rat cortex and hippocampus. Thus, bnip3 may be a mediator of developmental apoptosis in the postnatal rat brain. (c) 2006 Elsevier B.V. All rights reserved.

关键词： bnip3 apoptosis postnatal naturally occurring cell death Bcl-2 brain

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Hypoxia induces the expression of the pro-apoptotic gene bnip3

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CELL DEATH AND DIFFERENTIATION 2001年第4期8卷 367-376页

作者： Guo, K Searfoss, G Krolikowski, D Pagnoni, M Franks, C Clark, K Yu, KT Jaye, M Ivashchenko, Y AVENTIS PHARMA Cardiovasc Biol D-65926 Frankfurt Germany

It has been shown that oxygen deprivation results in apoptotic cell death, and that hypoxia inducible factor 1 (HIF1) and the tumor suppressor p53 play key roles in this process. However, the molecular mechanism through which hypoxia and HIF1 induce apoptosis is not clear. Here we show that the expression of pro-apoptotic gene bnip3 is dramatically induced by hypoxia in various cell types, including primary rat neonatal cardiomyocytes. Overexpression of HIF1 alpha, but not p53, induces the expression of bnip3, Overexpression of bnip3 leads to a rather unusual type of apoptosis, as no cytochrome c leakage from mitochondria was detected and inhibitors of caspases were unable to prevent cell death. Taken together, these data suggest that HIF1-dependent induction of bnip3 may play a significant role during hypoxia-induced cell death.

关键词： bnip3 hypoxia cardiomyocytes apoptosis

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Epigallocatechin-3-gallate attenuates apoptosis and autophagy in concanavalin A-induced hepatitis by inhibiting bnip3

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DRUG DESIGN DEVELOPMENT AND THERAPY 2016年第20160215期10卷 631-647页

作者： Li, Sainan Xia, Yujing Chen, Kan Li, Jingjing Liu, Tong Wang, Fan Lu, Jie Zhou, Yingqun Guo, Chuanyong Tongji Univ Sch Med Shanghai Peoples Hosp 10 Dept Gastroenterol Shanghai 200072 Peoples R China

Background: Epigallocatechin-3-gallate (EGCG) is the most effective compound in green tea, and possesses a wide range of beneficial effects, including anti-inflammatory, antioxidant, antiobesity, and anticancer effects. In this study, we investigated the protective effects of EGCG in concanavalin A (ConA)-induced hepatitis in mice and explored the possible mechanisms involved in these effects. Methods: Balb/C mice were injected with ConA (25 mg/kg) to induce acute autoimmune hepatitis, and EGCG (10 or 30 mg/kg) was administered orally twice daily for 10 days before ConA injection. Serum liver enzymes, proinflammatory cytokines, and other marker proteins were determined 2, 8, and 24 hours after the ConA administration. Results: bnip3 mediated cell apoptosis and autophagy in ConA-induced hepatitis. EGCG decreased the immunoreaction and pathological damage by reducing inflammatory factors, such as TNF-alpha, IL-6, IFN-gamma, and IL-1 beta. EGCG also exhibited an antiapoptotic and antiautophagic effect by inhibiting bnip3 via the IL-6/JAKs/STAT3 pathway. Conclusion: EGCG attenuated liver injury in ConA-induced hepatitis by downregulating IL-6/JAKs/STAT3/bnip3-mediated apoptosis and autophagy.

关键词： concanavalin A hepatitis EGCG autophagy apoptosis bnip3 STAT3 JAKs IL-6

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Membrane translocation and oligomerization of hBok are triggered in response to apoptotic stimuli and bnip3

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CELLULAR AND MOLECULAR LIFE SCIENCES 2005年第9期62卷 1015-1024页

作者： Gao, S Fu, W Dürrenberger, M De Geyter, C Zhang, H Univ Basel Dept Res CH-4031 Basel Switzerland Univ Basel Univ Womens Hosp CH-4031 Basel Switzerland Univ Zurich Hosp Med Res Ctr CH-8091 Zurich Switzerland Univ Basel Bioctr CH-4031 Basel Switzerland

hBok is a human pro-apoptotic member of the Bcl-2 family. By fluorescence in situ hybridization and in silico analysis, hBok was found to be located on chromosome 2q37.3. Its expression was detected in various organs and several hormonally regulated cancer cells. Expression of hBok was shown to be upregulated in estrogen-dependent breast cancer by estrogen deprivation and in myocardial cells during hypoxia. Confocal laser scanning microscopy examinations and subcellular fractionation studies showed that hBok was distributed in both the cytosol and intracellular membranes of healthy cells. Upon overexpression of hBok or stimulation of apoptosis, hBok became integrated into the membrane. Furthermore, apoptosis and oligomerization were promoted by BH3-only proteins, such as Bid, bnip3 and p53, but prevented by BFL-1. hBok was found to interact with bnip3. Our findings suggest that functional BH3-only proteins facilite the oligomerization and insertion of hBok into the membrane to activate it.

关键词： hBok apoptosis bnip3 subcellular localization oligomerization

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Ellagic acid antagonizes bnip3-mediated mitochondrial injury and necrotic cell death of cardiac myocytes

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FREE RADICAL BIOLOGY AND MEDICINE 2017年 112卷 411-422页

作者： Dhingra, Abhinav Jayas, Rahul Afshar, Pegah Guberman, Matthew Maddaford, Graham Gerstein, Johnathan Lieberman, Brooke Nepon, Hilary Margulets, Victoria Dhingra, Rimpy Kirshenbaum, Lorrie A. St Boniface Gen Hosp Albrechtsen Res Ctr Dept Physiol & Pathophysiol Inst Cardiovasc Sci Winnipeg MB Canada Univ Manitoba Coll Med Fac Hlth Sci Winnipeg MB R2H 2H6 Canada

The Bcl-2 protein bnip3 is crucial for provoking oxidative injury to mitochondria following anthracycline treatment or ischemia-reperfusion injury. Herein, we investigate the effects of the polyphenolic compound ellagic acid (EA) on bnip3 mediated mitochondrial injury and necrotic cell death in cardiac myocytes. In contrast to vehicle treated cardiomyocytes, bnip3 was highly enriched in mitochondrial fractions of cardiac myocytes treated with the anthracycline doxorubicin or in cells subjected to hypoxia (HPX). Mitochondrial associated bnip3 was accompanied by mPTP opening and loss of Delta psi m. The dynamin related fission protein Drp-1 was phosphorylated (Drp1(616)) and coincided with excessive mitochondrial fragmentation, mitophagy and necrosis in cardiac myocytes treated with doxorubicin or subjected to hypoxia. Moreover, knock-down of bnip3 was sufficient to prevent mitochondrial fission and doxorubicin-induced cell death supporting the involvement of bnip3 in doxorubicin cardiotoxity. Interestingly, mitochondrial associated bnip3 in cells treated with doxorubicin was markedly reduced by EA. This resulted in significantly less mitochondrial fission and cell death. Notably, EA similarly suppressed mitochondrial injury and cell death induced by hypoxia or bnip3 over-expression. Herein, we identify a novel signaling axis that operationally links EA and bnip3 for suppression of cardiac cell death. We provide compelling new evidence that EA suppresses mitochondrial injury and necrotic cell death of cardiac myocytes by functionally abrogating bnip3 activity. Hence, by suppressing mitochondrial injury induced by bnip3, EA may provide a therapeutic advantage in reducing oxidative injury and cardiac dysfunction in cancer patients undergoing anthracycline treatment or individuals with ischemic cardiac stress.

关键词： Ventricular myocytes Oxidative stress Mitochondria Mitophagy Cell death bnip3

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The HIF1α-inducible pro-cell death gene bnip3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

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ONCOGENE 2009年第41期28卷 3671-3680页

作者： Farrall, A. L. Whitelaw, M. L. Univ Adelaide Discipline Biochem Sch Mol & Biomed Sci Adelaide SA 5005 Australia Ctr Mol Genet Dev Adelaide SA Australia

The short isoform of single-minded 2 (SIM2s), a basic helix-loop-helix/PAS (bHLH/PAS) transcription factor, is upregulated in pancreatic and prostate tumours;however, a mechanistic role for SIM2s in these cancers is unknown. Microarray studies in prostate DU145 cells identified the pro-cell death gene, bnip3 (Bcl-2/adenovirus E1B 19 kDa interacting protein 3), as a novel putative target of SIM2s repression. Further validation showed bnip3 repression in several prostate and pancreatic carcinoma-derived cell lines with ectopic expression of human SIM2s. bnip3 levels are enhanced in prostate carcinoma cells upon short interfering (si) RNA-mediated knockdown of endogenous SIM2s. Chromatin immunoprecipitation and promoter studies show that SIM2s represses bnip3 through its activities at the proximal promoter hypoxia response element (HRE), the site through which the bHLH/PAS family member, hypoxia-inducible factor 1 alpha (HIF1 alpha), induces bnip3. SIM2s attenuates bnip3 hypoxic induction via the HRE, and increased hypoxic induction of bnip3 occurs with siRNA knockdown of endogenous SIM2s in prostate PC3AR+ cells. bnip3 is implicated in hypoxia-induced cell death processes. Prolonged treatment of PC3AR+ cells with hypoxia mimetics, DP and DMOG, confers hypoxia-induced autophagy, measured by enhanced LC3-II levels and SQSTM1/p62 turnover. We show that PC3AR+ cells expressing ectopic SIM2s have enhanced survival in these conditions. Induction of LC3-II and turnover of SQSTM1/p62 are attenuated in PC3AR+/SIM2s DMOG and hypoxia-treated cells, suggesting that SIM2s may attenuate autophagic cell death processes, perhaps through bnip3 repression. These data show, for the first time, SIM2s cross-talk on an endogenous HRE. SIM2s' functional interference with HIF1 alpha activities on bnip3 may indicate a novel role for SIM2s in promoting tumourigenesis. Oncogene (2009) 28, 3671-3680;doi: 10.1038/onc.2009.228;published online 10 August 2009

关键词： SIM2 bnip3 HIF1 alpha hypoxia cell death cancer

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Hypoxia suppresses myocardial survival pathway through HIF-1α-IGFBP-3-dependent signaling and enhances cardiomyocyte autophagic and apoptotic effects mainly via FoxO3a-induced bnip3 expression

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GROWTH FACTORS 2016年第3-4期34卷 73-86页

作者： Feng, Chih-Chung Lin, Chien-Chung Lai, Yi-Ping Chen, Tung-Sheng Asokan, Shibu Marthandam Lin, Jing-Ying Lin, Kuan-Ho Viswanadha, Vijaya Padma Kuo, Wei-Wen Huang, Chih-Yang China Med Univ Grad Inst Clin Med Sci Grad Inst Basic Med Sci Taichung Taiwan Armed Forces Gen Hosp Dept Orthopaed Taichung Taiwan China Med Univ Grad Inst Basic Med Sci Taichung Taiwan China Med Univ Hosp Biomat Translat Res Ctr Taichung Taiwan Cent Taiwan Univ Sci & Technol Dept Nursing Taichung Taiwan China Med Univ Hosp Emergency Dept Taichung Taiwan Bharathiar Univ Dept Biotechnol Coimbatore Tamil Nadu India China Med Univ Dept Biol Sci & Technol Taichung Taiwan China Med Univ Grad Inst Chinese Med Sci Taichung Taiwan Asia Univ Dept Hlth & Nutr Biotechnol Taichung Taiwan

The HIF-1 alpha transcriptional factor and the BH-3 only protein bnip3 are known to play fundamental roles in response to hypoxia. The objective of this research is to investigate the molecular mechanisms and the correlation of HIF-1 alpha, bnip3 and IGFBP-3 in hypoxia-induced cardiomyocytes injuries. Heart-derived H9c2 cells and neonatal rat ventricular myocytes (NRVMs) were incubated in normoxic or hypoxic conditions. Hypoxia increased HIF-1 alpha expression and activated the downstream bnip3 and IGFBP-3 thereby triggered mitochondria dependent apoptosis. Moreover, IGF1R/PI3K/Akt signaling was attenuated by HIF-1 alpha-dependent IGFBP-3 expression to enhance hypoxia-induced apoptosis. Autophagy suppression with 3-methyladenine or siATG5 or siBeclin-1 significantly decreased myocardial apoptosis under hypoxia. Knockdown of Fox03a or bnip3 significantly abrogated hypoxia-induced autophagy and mitochondria-dependent apoptosis. Moreover, prolonged-hypoxia induced H1F-1 alpha stimulated bnip3 and enhanced IGFBP-3 activation to inhibit IGF1R/P13K/Akt survival pathway and mediate mitochondria-dependent cardiomyocyte apoptosis. H1F-1 alpha and Fox03a blockage are sufficient to annul the change of excessive hypoxia of hearts.

关键词： Hypoxia bnip3 IGFBP-3 autophagy apoptosis

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Platonin protects against cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasomes via bnip3/LC3 signaling mediated autophagy

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BRAIN RESEARCH BULLETIN 2022年第0期180卷 12-23页

作者： Luo, Jing Tan, Junyi Jiang, Ning Yang, Changhong Chen, Jialei Zhao, Jing Li, Lingyu Zhao, Yong Chongqing Med Univ Dept Pathol Chongqing 400016 Peoples R China Chongqing Med Univ Dept Pathophysiol Chongqing 400016 Peoples R China Chongqing Med Univ Dept Bioinformat Chongqing 400016 Peoples R China Chongqing Med Univ Inst Neurosci Chongqing 400016 Peoples R China

Studies have found that Platonin has neuroprotective effect, but its molecular mechanism needs further study. We found that at the early stage of cerebral ischemia/reperfusion injury, Platonin treatment significantly reduced cerebral infarct lesions, improved neurological scores, and exerted neuroprotective effects. Our group has shown that NLRP3 inflammasomes activation is required to mediate neuronal injury during cerebral ischemia /reperfusion injury. The brain protective effect of Platonin is related to its ability to effectively regulate autophagy and NLRP3 inflammasomes-derived inflammation. Platonin treatment effectively induced autophagy (LC3II/I, p62) and reduced NLRP3 inflammasomes activation(NLRP3, cleaved-IL-113,cleaved-IL-18, cleaved-caspase1). However, 3-MA (15 mg/kg) treatment downregulated the inhibitory effect of Platonin on NLRP3 inflammasomes. We also studied the location of bnip3 in Platonin-mediated neuroprotection and found that Platonin induced the expression of autophagic protein bnip3 and enhanced the co-immunoprecipitation of bnip3 with LC3, and double-labeled immunofluorescence also showed enhanced co-localization of bnip3 with LC3. Finally, si-bnip3 transfection attenuated the co localization of bnip3 with LC3, decreased the autophagy activity to a certain extent and blocked the inhibition of NLRP3 inflammasomes-derived inflammation by Platonin. This study demonstrated that Platonin may play a neuroprotection role in cerebral I / R injury by inhibiting NLRP3 inflammasomes activation through upregulating autophagy via bnip3 / LC3 pathway.

关键词： Platonin bnip3 LC3 Autophagy NLRP3 inflammasomes Inflammation Neuroprotection Cerebral I R injury

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