title: JNK- and Akt-mediated Puma expression in the apoptosis of cisplatin-resistant ovarian cancer cells.
abstract: BH3 (Bcl-2 homology domain 3)-only proteins have an important role in the cisplatin resistance of cells. However, the effect of BH3-only proteins on cisplatin-resistant ovarian cancer cells has not been thoroughly elucidated. Our results from the present study indicate that Puma plays a critical role in the apoptosis of chemo-resistant ovarian cancer cells treated with BetA (betulinic acid). The reduction of Puma expression inhibits Bax activation and apoptosis. However, p53 gene silencing has little effect on Puma activation. Further experiments demonstrated that Akt-mediated FoxO3a (forkhead box O3a) nuclear translocation and the JNK (c-Jun N-terminal kinase)/c-Jun pathway only partially trigger Puma induction and apoptosis, whereas dominant-negative c-Jun expression with FoxO3a reduction completely inhibits Puma expression and cell death. Furthermore, our results suggest that JNK regulates the Akt/FoxO3a signalling pathway. Therefore the dual effect of JNK can efficiently trigger Puma activation and apoptosis in chemoresistant cells. Taken together, our results demonstrate the role of Puma in BetA-induced apoptosis and the molecular mechanisms of Puma expression regulated by BetA during ovarian cancer cell apoptosis. Our findings suggest that the JNK-potentiated Akt/FoxO3a and JNK-mediated c-Jun pathways co-operatively trigger Puma expression, which determines the threshold for overcoming chemoresistance in ovarian cancer cells.
authors.affiliation: The State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Hitech District, Sichuan University, Chengdu, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Zhao
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Tang
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhong
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Wenbin
authors.initials: W
authors.lastname: Hu
authors.forename: Zhu
authors.initials: Z
authors.lastname: Yuan
authors.forename: Chunlai
authors.initials: C
authors.lastname: Nie
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D002945:Cisplatin