title: The p53 upregulated modulator of apoptosis (PUMA) chemosensitizes intrinsically resistant ovarian cancer cells to cisplatin by lowering the threshold set by Bcl-x(L) and Mcl-1.
abstract: Ovarian cancer is the number one cause of death from gynecologic malignancy. A defective p53 pathway is a hallmark of ovarian carcinoma. The p53 mutation correlates significantly with resistance to platinum-based chemotherapy, early relapse and shortened overall survival in ovarian cancer patients. PUMA (p53 upregulated modulator of apoptosis), a BH3-only Bcl-2 family protein, was recently identified as a transcriptional target of p53 and a potent apoptosis inducer in various cancer cells. In this study, we showed that the induction of PUMA by cisplatin was abolished in p53-deficient SKOV3 cells. Elevated expression of PUMA-induced apoptosis and sensitized A2780s and SKOV3 ovarian cancer cells to cisplatin, and the combination of PUMA and low-dose cisplatin, significantly suppressed xenograft tumor growth in vivo through enhanced induction of apoptosis compared with treatment with PUMA or cisplatin alone. The effects of PUMA were mediated by enhanced caspase activation and release of cytochrome c and Smac (second mitochondria-derived activator of caspase) into the cytosol. Furthermore, PUMA chemosensitized intrinsically resistant SKOV3 cells to cisplatin through downregulation of B-cell lymphoma-extra large (Bcl-x(L)) and myeloid cell leukemia sequence 1 (Mcl-1). PUMA-mediated Bcl-x(L) downregulation mainly happened at the transcription level, whereas PUMA-induced Mcl-1 down-regulation was associated with caspase-dependent cleavage and proteasome-mediated degradation. To our knowledge, these data suggest a new mechanism by which overexpression of PUMA enhances sensitivity of SKOV3 cells to cisplatin by lowering the threshold set simultaneously by Bcl-x(L) and Mcl-1. Taken together, our findings indicate that PUMA is an important modulator of therapeutic responses of ovarian cancer cells and is potentially useful as a chemosensitizer in ovarian cancer therapy.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China. yuanzhujyx@gmail.com
authors.forename: Zhu
authors.initials: Z
authors.lastname: Yuan
authors.forename: Kang
authors.initials: K
authors.lastname: Cao
authors.forename: Chao
authors.initials: C
authors.lastname: Lin
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Huan-yi
authors.initials: HY
authors.lastname: Liu
authors.forename: Xin-yu
authors.initials: XY
authors.lastname: Zhao
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Hong-xin
authors.initials: HX
authors.lastname: Deng
authors.forename: Jiong
authors.initials: J
authors.lastname: Li
authors.forename: Chun-lai
authors.initials: CL
authors.lastname: Nie
authors.forename: Yu-quan
authors.initials: YQ
authors.lastname: Wei
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D006801:Humans; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; C579095:MCL1 protein, human; D024101:Mitochondrial Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D045304:Cytochromes c; D020169:Caspases; D002945:Cisplatin