Targeted inhibition of FAK, PYK2 and BCL-XL synergistically enhances apoptosis in ovarian clear cell carcinoma cell lines.
Targeted inhibition of FAK, PYK2 and BCL-XL synergistically enhances apoptosis in ovarian clear cell carcinoma cell lines.
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DOI：
10.1371/journal.pone.0088587
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kim BG
中科院分区：
文献类型：
--
作者：
Yoon H;Choi YL;Song JY;Do I;Kang SY;Ko YH;Song S;Kim BG
卵巢透明细胞癌(OCCC)对一线化疗具有较高的耐药性，需要开发新的治疗方法。我们以前在8q24发现了一个频繁的染色体获得，该染色体含有粘着斑激酶(FAK)基因；该基因作为OCCS治疗靶点的潜力仍有待评估。我们首先研究了OCCCs对FAK和PI3K/AKT信号通路的依赖性。在67例OCCC标本中，有20%的标本FAK过表达，且这种过表达与其拷贝数增加有关。FAK拷贝数增加和PIK3CA突变约占OCCC样本的40%，这表明FAK/PI3K/AKT轴是一个有吸引力的靶向治疗候选基因。因此，我们用FAK抑制剂PF-562,271(PF271)和PF-573,228(PF228)处理卵巢癌细胞系，包括OCCC亚型。卵巢癌细胞对PF271比对PF228更敏感。然后，我们寻找与PF271联合使用对细胞死亡具有协同作用的单一药物。我们发现，pF271与bcl2/bclxl拮抗剂ABT-737联合作用能显著诱导细胞凋亡。RMGI和OVISE细胞对ABT-737的敏感性高于存在PIK3CA突变的OVMANA和SKOV3细胞。在机制上，PF271通过PI3K/AKT途径导致抗凋亡蛋白MCL1一过性下调。因此，PF271/ABT-737处理导致抗凋亡蛋白MCL1和BCL-XL/BCL-2的抑制。我们认为，药物抑制bclxl和FAK/PYK2可能是治疗口腔癌的一种潜在的治疗策略。
Ovarian clear cell carcinoma (OCCC) displays a higher resistance to first line chemotherapy, requiring the development of new therapeutics. We previously identified a frequent chromosomal gain at 8q24 that harbors the focal-adhesion kinase (FAK) gene; the potential of this gene as a therapeutic target remains to be evaluated in OCCCs. We first examined the dependence of OCCCs on FAK and the PI3K/AKT signaling pathway. FAK was overexpressed in 20% of 67 OCCC samples, and this overexpression was correlated with its copy number gain. FAK copy number gains and mutations in PIK3CA accounted for about 40% of OCCC samples, suggesting that the FAK/PI3K/AKT axis is an attractive candidate for targeted therapeutics. We, therefore, treated ovarian cancer cell lines, including OCCC subtypes, with the FAK inhibitors PF-562,271 (PF271), and PF-573,228 (PF228). Ovarian cancer cells were more sensitive to PF271 than PF228. We then searched for single agents that exhibited a synergistic effect on cell death in combination with PF271. We found that co-treatment of PF271 with ABT-737, a BCL-2/BCL-XL antagonist, was profoundly effective at inducing apoptosis. RMGI and OVISE cells were more sensitive to ABT-737 than OVMANA and SKOV3 cells, which have PIK3CA mutations. Mechanistically, PF271 treatment resulted in the transient down-regulation of the anti-apoptotic protein MCL1 via the PI3K/AKT pathway. Therefore, PF271/ABT-737 treatment led to the inhibition of the anti-apoptotic proteins MCL1 and BCL-XL/BCL-2. We suggest that pharmacological inhibition of BCL-XL and FAK/PYK2 can be a potential therapeutic strategy for the treatment of OCCC.
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影响因子：
64.8
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
通讯作者：
Wei, Wenyi
影响因子：
11.2
作者：
Roberts, Walter Gregory;Ung, Ethan;Vajdos, Felix
通讯作者：
Vajdos, Felix
影响因子：
4.8
作者：
Slack-Davis, Jill K.;Martin, Karen H.;Parsons, J. Thomas
通讯作者：
Parsons, J. Thomas
影响因子：
4.7
作者：
Dodier, P;Piché, A
通讯作者：
Piché, A
DOI：
10.1126/science.1196333
发表时间：
2010-10-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jones S;Wang TL;Shih IeM;Mao TL;Nakayama K;Roden R;Glas R;Slamon D;Diaz LA Jr;Vogelstein B;Kinzler KW;Velculescu VE;Papadopoulos N
通讯作者：
Papadopoulos N