Dual inhibiting OCT4 and AKT potently suppresses the propagation of human cancer cells.
Dual inhibiting OCT4 and AKT potently suppresses the propagation of human cancer cells.
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双重抑制 OCT4 和 AKT 可有效抑制人类癌细胞的增殖
DOI：
10.1038/srep46246
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发表时间：
2017-04-06
影响因子：
4.6
通讯作者：
Wang YJ
中科院分区：
文献类型：
--
作者：
Li W;Zhou Y;Zhang X;Yang Y;Dan S;Su T;She S;Dong W;Zhao Q;Jia J;Yao H;Zheng M;Kang B;Wang YJ
AKT作为一种表观遗传调节剂，将表观遗传调节与细胞存活和增殖联系起来，而表观遗传介导剂OCT 4则严格控制干细胞多能性和自我更新。新出现的证据表明，它们在癌细胞和癌症干细胞（CSC）中的复杂相互作用，抑制其中一种可能会激活另一种。因此，在这项研究中，我们提出了一个战略，同时针对这两个因素。首先，OCT 4特异性shRNA和特异性AKT抑制剂Akti-1/2的组合有效地抑制了人胚胎癌细胞、贴壁癌细胞和干细胞样癌细胞的增殖，建立了双重抑制OCT 4和AKT可以有效靶向各种癌细胞的概念验证。接下来，我们将Akti-1/2与二甲双胍结合，二甲双胍是一种广泛用于治疗2型糖尿病的药物，据报道可以下调OCT 4的表达。二甲双胍+ Akti-1/2组合显著改变多种信号传导和表观遗传途径，诱导粘附和干细胞样胶质母细胞瘤U87细胞的生长停滞和细胞死亡，并减弱其体内致瘤性。总之，我们在此证明，通过双重抑制OCT 4和AKT，同时靶向表观遗传介质和表观遗传调节剂，可以在抑制CSC以及整个分化癌细胞的增殖方面具有比单一治疗显著改善的功效。
AKT serves as an epigenetic modulator that links epigenetic regulation to cell survival and proliferation while the epigenetic mediator OCT4 critically controls stem cell pluripotency and self-renewal. Emerging evidence indicated their complicated interplays in cancer cells and cancer stem cells (CSCs), and inhibiting either one may activate the other. Thus, in this study, we propose a strategy to targeting both factors simultaneously. Firstly, a combination of an OCT4-specific shRNA and the specific AKT inhibitor Akti-1/2 potently suppressed the propagation of human embryonal carcinoma cells, adherent cancer cells and stem-like cancer cells, establishing the proof-of-concept that dual inhibiting OCT4 and AKT can effectively target various cancer cells. Next, we combined Akti-1/2 with metformin, a widely-prescribed drug for treating type 2 diabetes, which was reported to down-regulate OCT4 expression. The metformin + Akti-1/2 combo significantly altered multiple signaling and epigenetic pathways, induced growth arrest and cell death of adherent and stem-like glioblastoma U87 cells, and attenuated their tumorigenicityin vivo. Taken together, we demonstrate here that simultaneously targeting an epigenetic mediator and an epigenetic modulator, by dual inhibiting OCT4 and AKT, can have significantly improved efficacies over single treatment in suppressing the propagation of CSCs as well as the entire bulk of differentiated cancer cells.