title: Phosphorylation of signal transducer and activator of transcription 1 reduces bortezomib-mediated apoptosis in cancer cells.
abstract: The potent and selective proteasome inhibitor bortezomib has shown remarkable antitumor activity and is now entering clinical trials for several cancers. However, the molecular mechanisms by which bortezomib induces cytotoxicity in ovarian cancer cells still remain unclear. In this study, we show that bortezomib induced apoptosis, which was demonstrated by the downregulation of antiapoptotic molecules (Bcl-2, Bcl-XL, p-Bad, and p-AKT) and the upregulation of proapoptotic proteins (p21, p27, and cleaved-Bid) in ovarian cancer cell lines. Moreover, bortezomib stimulates Janus kinase (JAK) phosphorylation and activates heat-shock transcription factor-1 (HSF-1) and heat-shock protein 70 (HSP70), ultimately leading to signal transducer and activator of transcription 1 (STAT1) phosphorylation. Phosphorylated STAT1 partially counteracted apoptosis induced by bortezomib in cancer cells. These findings suggest that the antitumor activity of bortezomib in ovarian cancer can be improved by inhibiting bortezomib-induced STAT1 phosphorylation. This effect can be achieved by STAT1 knockdown, HSP70 knockdown, JAK inhibition, or the addition of cisplatin, one of the most commonly used anticancer drugs. These results provide the first evidence that STAT1 phosphorylation can play a role in bortezomib resistance by exerting antiapoptotic effects. They also suggest the possibility to abolish or reduce bortezomib chemoresistance in ovarian cancer by the addition of cisplatin or JAK inhibitors.
authors: Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan 333, Republic of China.
authors: C
authors: C
authors: Kao
authors: A
authors: A
authors: Chao
authors: C L
authors: CL
authors: Tsai
authors: C Y
authors: CY
authors: Lin
authors: W C
authors: WC
authors: Chuang
authors: H W
authors: HW
authors: Chen
authors: T C
authors: TC
authors: Yen
authors: T H
authors: TH
authors: Wang
authors: C H
authors: CH
authors: Lai
authors: H S
authors: HS
authors: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000627:therapeutic use / Q000633:toxicity*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011719:Pyrazines / Q000627:therapeutic use / Q000633:toxicity*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D011719:Pyrazines; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D014157:Transcription Factors; D000069286:Bortezomib; D053612:Janus Kinases; D002945:Cisplatin