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.
Highlights
Signal transducer and activator of transcription 1 (STAT1), a member of a family of latent cytoplasmic transcription factors, has a crucial role in a variety of biological functions, including cell proliferation and apoptosis.[8,9] It has been demonstrated that interferons or interleukins can activate Janus kinase (JAK) and Tyk[2], which is followed by tyrosine phosphorylation of different STAT family members (STAT1, STAT2, and STAT3).[9]
We systematically surveyed the signaling pathways regulated by bortezomib and demonstrated for the first time that the inhibition of STAT1 enhances bortezomibinduced cytotoxicity in ovarian cancer cells (Figure 7)
We investigated the molecular mechanisms of bortezomib-induced cell death in ovarian cancer cells using a panel of 11 reporter assays examining different signaling
Summary
Signal transducer and activator of transcription 1 (STAT1), a member of a family of latent cytoplasmic transcription factors, has a crucial role in a variety of biological functions, including cell proliferation and apoptosis.[8,9] It has been demonstrated that interferons or interleukins can activate Janus kinase (JAK) and Tyk[2], which is followed by tyrosine phosphorylation of different STAT family members (STAT1, STAT2, and STAT3).[9]. In a phase I study, the combination of bortezomib and carboplatin elicited an overall response rate of 47% in recurrent ovarian or primary peritonealcancer[17] Notably, bortezomib has been shown to induce ovarian cancer cell death by decreasing the levels of Bcl-XL and X-linked inhibitor of apoptosis protein.[18] In addition, bortezomib has the ability to promote cell cycle arrest and apoptosis through the induction of p21/p27 and the activation of caspase-3.16 Despite these promising results, a Gynecologic Oncology Group phase II trial has reported that bortezomib has minimal activity as a single agent in the treatment of recurrent platinum-sensitive epithelial ovarian or primary peritoneal cancer.[19] Importantly, the molecular mechanisms underlying the antineoplastic effects of bortezomib (either alone or in combination with other drugs) have not yet been completely elucidated
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