Phosphorylation of signal transducer and activator of transcription 1 reduces bortezomib-mediated apoptosis in cancer cells.
Phosphorylation of signal transducer and activator of transcription 1 reduces bortezomib-mediated apoptosis in cancer cells.
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DOI：
10.1038/cddis.2013.38
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发表时间：
2013-02-28
影响因子：
9
通讯作者：
Wang, H. S.
中科院分区：
文献类型：
--
作者：
Kao, C.;Chao, A.;Tsai, C. L.;Lin, C. Y.;Chuang, W. C.;Chen, H. W.;Yen, T. C.;Wang, T. H.;Lai, C. H.;Wang, H. S.
有效的选择性蛋白酶体抑制剂硼替佐米已显示出显着的抗肿瘤活性，目前正在进入多种癌症的临床试验。然而，硼替佐米诱导卵巢癌细胞细胞毒性的分子机制仍不清楚。在这项研究中，我们发现硼替佐米诱导细胞凋亡，这通过卵巢癌细胞系中抗凋亡分子（Bcl-2、Bcl-XL、p-Bad 和 p-AKT）的下调和促凋亡蛋白（p21、p27 和 cleaved-Bid）的上调来证明。此外，bortezomib 刺激 Janus 激酶 (JAK) 磷酸化并激活热休克转录因子 1 (HSF-1) 和热休克蛋白 70 (HSP70)，最终导致信号转导器和转录激活剂 1 (STAT1) 磷酸化。磷酸化的 STAT1 部分抵消了硼替佐米诱导的癌细胞凋亡。这些发现表明，硼替佐米在卵巢癌中的抗肿瘤活性可以通过抑制硼替佐米诱导的 STAT1 磷酸化来提高。这种效果可以通过 STAT1 敲低、HSP70 敲低、JAK 抑制或添加最常用的抗癌药物之一顺铂来实现。这些结果提供了第一个证据，证明 STAT1 磷酸化可以通过发挥抗细胞凋亡作用在硼替佐米耐药中发挥作用。他们还提出了通过添加顺铂或 JAK 抑制剂来消除或减少卵巢癌中硼替佐米化疗耐药性的可能性。
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.
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DOI：
10.1158/1078-0432.ccr-08-2081
发表时间：
2009-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jandial DD;Farshchi-Heydari S;Larson CA;Elliott GI;Wrasidlo WJ;Howell SB
通讯作者：
Howell SB
影响因子：
4.8
作者：
Fribley, Andrew M.;Evenchik, Benjamin;Wang, Cun-Yu
通讯作者：
Wang, Cun-Yu
影响因子：
11.4
作者：
Monaghan, K. A.;Khong, T.;Spencer, A.
通讯作者：
Spencer, A.
影响因子：
11.2
作者：
Bazzaro, M;Lee, MK;Roden, RBS
通讯作者：
Roden, RBS
影响因子：
4.4
作者：
Baritaki, Stavroula;Suzuki, Eriko;Bonavida, Benjamin
通讯作者：
Bonavida, Benjamin