Prohibitin silencing reverses stabilization of mitochondrial integrity and chemoresistance in ovarian cancer cells by increasing their sensitivity to apoptosis

Gregory-Bass, Rosalind; Olatinwo, Moshood; Xu, Wei; Matthews, Roland; Stiles, Jonathan K.; Thomas, Kenneth W.; Liu, Dong; Tsang, Benjamin K.; Thompson, Winston E.

doi:10.1002/ijc.23351

Cited by 70 publications

(73 citation statements)

References 38 publications

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“…30 In addition, PHB1 inhibits staurosporine-induced apoptosis and promotes survival in ovarian cancer cells. 31 Consistent with previous findings, our study shows that PHB1 inhibits H 2 O 2 -induced apoptosis in cardiomyocytes. Thus, (h and i) MiR-361 transgenic mice exhibit increased mitochondrial fission, apoptosis and myocardial infarction sizes in response to ischemia injury.…”

Section: Phb1supporting

confidence: 93%

miR-361-regulated prohibitin inhibits mitochondrial fission and apoptosis and protects heart from ischemia injury

Wang

Liu

et al. 2014

Cell Death Differ

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Cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Emerging evidences suggest that the abnormal mitochondrial fission participates in pathogenesis of cardiac diseases, including myocardial infarction (MI) and heart failure. However, the molecular components regulating mitochondrial network in the heart remain largely unidentified. Here we report that miR-361 and prohibitin 1 (PHB1) constitute an axis that regulates mitochondrial fission and apoptosis. The results show that PHB1 attenuates mitochondrial fission and apoptosis in response to hydrogen peroxide treatment in cardiomyocytes. Cardiac-specific PHB1 transgenic mice show reduced mitochondrial fission and myocardial infarction sizes after myocardial infarction surgery. MiR-361 is responsible for the dysfunction of PHB1 and suppresses the translation of PHB1. Knockdown of miR-361 reduces mitochondrial fission and apoptosis in vivo and in vitro. MiR-361 cardiac-specific transgenic mice represent elevated mitochondrial fission and myocardial infarction sizes upon myocardial ischemia injury. This study identifies a novel signaling pathway composed of miR-361 and PHB1 that regulates mitochondrial fission program and apoptosis. This discovery will shed new light on the therapy of myocardial infarction and heart failure. The heart drives the blood flow in the body and it has a large requirement of energy. Mitochondria meet the high energy demand of the heart by consistently providing large amounts of ATP through oxidative phosphorylation. Thus, mitochondrial malfunction is tightly related to cardiac diseases and contributes to cardiomyocyte injury, cardiomyopathy and heart failure. Mitochondria morphology is also associated with the function. Mitochondria constantly undergo fission and fusion. Fission leads to the formation of small round mitochondria and promotes cell apoptosis, 1-7 whereas fusion results in mitochondria elongation and have a protective role in cardiomyocytes maintenance. 8 The above findings strongly suggest that mitochondrial fission and fusion machinery is important for cardiac function. In addition, unveiling the mechanism of mitochondrial network regulation will provide a novel therapeutic strategy for heart failure.The mitochondrial prohibitin complex is a macromolecular structure at the inner mitochondrial membrane that is composed of prohibitin 1 (PHB1) and prohibitin 2 subunits. 9These two proteins comprise an evolutionary conserved and ubiquitously expressed family of membrane proteins and are implicated in several important cellular processes such as mitochondrial biogenesis and function, cell proliferation, replicative senescence, and cell death.10,11 The first mammalian PHB1 was identified as a potential tumor suppressor with anti-proliferative activity.12 Recent findings suggest that PHB1 has an important role in regulating mitochondrial morphology.Loss of PHB1 results in accumulation of fragmented mitochondria in MEFs and HeLa cells.13,14 However, it is not yet clear whether PHB1 participates in ...

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Section: Phb1supporting

confidence: 93%

miR-361-regulated prohibitin inhibits mitochondrial fission and apoptosis and protects heart from ischemia injury

Wang

Liu

et al. 2014

Cell Death Differ

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“…In contrast to those in normal ovarian epithelium, a higher prohibitin expression level was observed in ovarian papillary serous and endometrioid carcinomas, which was inversely associated with cellular Ki-67 expression, a marker of cell proliferation and positively correlated with the cell survival marker X-linked inhibitor of apoptosis protein (XIAP). Prohibitin may be a negative regulator of cell growth and function as an antiapoptotic factor in ovarian cancer cells, as well as play an important role in determining the chemosensitivity of ovarian cancer cells [25]. In this study, we showed that prohibitin was specifically up-regulated by LH in ovarian epithelial cells by a proteomic method.…”

Section: Discussionmentioning

confidence: 63%

Prohibitin as a novel target protein of luteinizing hormone in ovarian epithelial carcinogenesis

Ji¹,

Yi²,

Zhang³

et al. 2011

neo

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The exact role of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in ovarian epithelial carcinoma (OEC) development has not been yet characterized. This prompted us to identify particular proteins to better understand the underlying mechanism. Total proteins from ovarian epithelial tumor (OET) cells treated with gonadotropins were analyzed by proteomics. Western blot and immunohistochemistry were used to validate the target protein (prohibitin) and to detect its expression in human ovarian tissue of serous tumors. As the results, prohibitin was found to be significantly up-regulated by LH, with a maximum of 2.5-fold increase at the concentration of 200 mIU/mL. The expression of prohibitin was steadily decreased from benign serous cystadenomas to borderline tumors and serous carcinomas (P < 0.0001). The difference between any two groups was significant (P < 0.001). Collectively, data from this study indicate that prohibitin is one LH-associated protein and it may be protective of ovarian cancer development and progression, supporting that LH may play an inhibitory role in ovarian tumorigenesis.

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“…PHB1 has been shown to have a role in the regulation of apoptosis (11,13). We therefore examined whether transient knockdown of PHB1 results in the activation of the apoptotic pathway after treatment with paclitaxel.…”

Section: Transient Silencing Of Gstπ and Phb1 Partially Rescues Paclimentioning

confidence: 99%

“…It resides at the inner mitochondrial membrane where it serves as a protein chaperone (9,10). Recently, studies have shown that PHB1 has a role in the regulation of the apoptotic pathway (11)(12)(13). Additionally prohibitins have been found to reside on the cell surface of certain cells, including adipose endothelial cells (14,15).…”

mentioning

confidence: 99%

Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells

Patel

Chatterjee

Vrbanac

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Paclitaxel has emerged as a front line treatment for aggressive malignancies of the breast, lung, and ovary. Successful therapy of cancer is frequently undermined by the development of paclitaxel resistance. There is a growing need to find other therapeutic targets to facilitate treatment of drug-resistant cancers. Using a proteomics approach, elevated levels of Prohibitin1 (PHB1) and GSTπ were found associated with paclitaxel resistance in discrete subcellular fractions of two drug-resistant sublines relative to their sensitive sublines. Immunofluorescence staining and fractionation studies revealed increased levels of PHB1 on the surface of resistant cell lines. Transiently silencing either PHB1 or GSTπ gene expression using siRNA in the paclitaxel-resistant cancer cell sublines partially sensitized these cells toward paclitaxel. Intriguingly, silencing PHB1 but not GSTπ resulted in activation of the intrinsic apoptosis pathway in response to paclitaxel. Similarly, stably silencing either PHB1 or GSTπ significantly improved paclitaxel sensitivity in A549TR cells both in vitro and in vivo. Our results indicate that PHB1 is a mediator of paclitaxel resistance and that this resistance may depend on the cellular localization of the protein. We suggest PHB1 as a potential target for therapeutic strategies for the treatment of drug-resistant tumors.apoptosis | glutathione-S-transferase Pi | mitochondria | plasma membrane | protein translocation

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Prohibitin silencing reverses stabilization of mitochondrial integrity and chemoresistance in ovarian cancer cells by increasing their sensitivity to apoptosis

Cited by 70 publications

References 38 publications

miR-361-regulated prohibitin inhibits mitochondrial fission and apoptosis and protects heart from ischemia injury

miR-361-regulated prohibitin inhibits mitochondrial fission and apoptosis and protects heart from ischemia injury

Prohibitin as a novel target protein of luteinizing hormone in ovarian epithelial carcinogenesis

Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells

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