Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells.
Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells.
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DOI：
10.1038/onc.2011.409
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发表时间：
2012-05-03
期刊：
影响因子：
8
通讯作者：
Turkson, J.
中科院分区：
文献类型：
--
作者：
Yue, P.;Zhang, X.;Paladino, D.;Sengupta, B.;Ahmad, S.;Holloway, R. W.;Ingersoll, S. B.;Turkson, J.
我们提供的证据表明，对顺铂耐药的人卵巢癌系A2780S/CP1 （S/CP1）、A2780S/CP3 （S/CP3）和A2780S/CP5 (S/CP5)，分别对1、3和5 μM顺铂耐药，经多轮顺铂治疗后恢复，具有增强的集落形成能力和改变的形态，这与体外运动、迁移和侵袭性增强一致。恶性表型随着耐药性的增加而发展，并与表皮生长因子受体(EGFR)/细胞外信号调节激酶（Erk）1/2和Janus激酶（Jaks）过度活跃、EGFR和Jaks促进的信号转导和转录激活因子（Stat） 3激活异常以及体外上皮-间质转化（EMT）有关。Survivin和FLIP抗凋亡因子、血管内皮生长因子（VEGF）和基质金属蛋白酶活性也在耐药细胞中升高。因此，在敏感的A2780S细胞中，组成活性Stat3C的异位表达降低了顺铂敏感性。抑制EGFR或Stat3活性可抑制Survivin、VEGF和Vimentin的表达以及耐药细胞的集落形成潜力、活力、运动性和迁移，并使其对顺铂敏感。对人卵巢癌患者肿瘤组织的分析显示，EGFR和Stat3异常活跃，在某些情况下与Vimentin过表达相关。腹腔内小鼠异种移植研究显示，与局限于卵巢的低肿瘤发生率的敏感的A2780S系相比，耐药的S/CP3和S/CP5系的肿瘤发生率高，它们在小肠和结肠的几个位置形成肿瘤结节，对顺铂的反应较差，但对顺铂和EGFR或Stat3抑制剂同时治疗敏感。过度活跃的EGFR信号通过Stat3和Jak-Stat3活性共同促进卵巢癌进展到顺铂耐药，因此代表了预防顺铂治疗期间卵巢癌顺铂耐药发展和复发疾病的靶点。
We present evidence that the cisplatin-resistant human ovarian cancer lines, A2780S/CP1 (S/CP1), A2780S/CP3 (S/CP3), and A2780S/CP5 (S/CP5), derived by subjecting the sensitive A2780S ovarian cancer line to multiple rounds of cisplatin treatments followed by recovery and are resistant to 1, 3, and 5 μM cisplatin, respectively, have increased colony-forming ability and altered morphology that is consistent with enhanced motility, migration, and invasiveness in vitro. The malignant phenotype progresses with increasing resistance and is associated with hyperactive epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (Erk)1/2 and Janus kinases (Jaks), aberrant Signal Transducer and Activator of Transcription (Stat) 3 activation promoted by EGFR and Jaks, and epithelial-mesenchymal transition (EMT) in vitro. Survivin and FLIP anti-apoptotic factors, vascular endothelial growth factor (VEGF), and matrix metalloproteinase activities are also elevated in the resistant cells. Accordingly, the ectopic expression of constitutively-active Stat3C in the sensitive A2780S cells diminished cisplatin sensitivity. The inhibition of EGFR or Stat3 activity repressed Survivin, VEGF and Vimentin expression and the colony-forming potential, viability, motility, and migration of the resistant cells, and sensitized them to cisplatin. Analysis of human ovarian cancer patients’ tumor tissues shows aberrantly-active EGFR and Stat3 that in certain cases correlate with Vimentin over-expression. Intra-peritoneal mouse xenograft studies revealed, compared to the sensitive A2780S line that had low tumor incidence restricted to the ovary, a high tumor incidence for the resistant S/CP3 and S/CP5 lines that formed tumor nodules at several locations on the small-intestine and colon, and which responded poorly to cisplatin, but were sensitive to concurrent treatment with cisplatin and EGFR or Stat3 inhibitor. Hyperactive EGFR signaling through Stat3 and the Jak-Stat3 activity together promote ovarian cancer progression to cisplatin resistance and therefore represent targets for preventing the development of cisplatin resistance and the recurrent disease during cisplatin therapy in ovarian cancer.
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