Yang F, Deng R, Qian X-J, Chang S-H, Wu X-Q, Qin J, Feng G-K, Ding K, Zhu X-F
1] State Key Laboratory of Oncology in South China, Collaborative Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China [2] Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
State Key Laboratory of Oncology in South China, Collaborative Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Cell Death Dis. 2014 Mar 13;5(3):e1114. doi: 10.1038/cddis.2014.43.
The serine/threonine kinase AKT is generally accepted as a promising anticancer therapeutic target. However, the relief of feedback inhibition and enhancement of other survival pathways often attenuate the anticancer effects of AKT inhibitors. These compensatory mechanisms are very complicated and remain poorly understood. In the present study, we found a novel 2-pyrimidyl-5-amidothiazole compound, DC120, as an ATP competitive AKT kinase inhibitor that suppressed proliferation and induced apoptosis in liver cancer cells both in vitro and in vivo. DC120 blocked the phosphorylation of downstream molecules in the AKT signal pathway in dose- and time-dependent manners both in vitro and in vivo. However, unexpectedly, DC120 activated mammalian target of rapamycin complex 1 (mTORC1) pathway that was suggested by increased phosphorylation of 70KD ribosomal protein S6 kinase (P70S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). The activated mTORC1 signal was because of increase of intracellular Ca(2+) via Ca(2+)/calmodulin (CaM)/ signaling to human vacuolar protein sorting 34 (hVps34) upon AKT inhibition. Meanwhile, DC120 attenuated the inhibitory effect of AKT on CRAF by decreasing phosphorylation of CRAF at Ser259 and thus activated the mitogen-activated protein kinase (MAPK) pathway. The activation of the mTORC1 and MAPK pathways by DC120 was not mutually dependent, and the combination of DC120 with mTORC1 inhibitor and/or MEK inhibitor induced significant apoptosis and growth inhibition both in vitro and in vivo. Taken together, the combination of AKT, mTORC1 and/or MEK inhibitors would be a promising therapeutic strategy for liver cancer treatment.
丝氨酸/苏氨酸激酶AKT通常被认为是一个很有前景的抗癌治疗靶点。然而，反馈抑制的解除和其他生存途径的增强常常会削弱AKT抑制剂的抗癌效果。这些补偿机制非常复杂，目前仍知之甚少。在本研究中，我们发现了一种新型的2-嘧啶基-5-氨基噻唑化合物DC120，它作为一种ATP竞争性AKT激酶抑制剂，在体外和体内均可抑制肝癌细胞的增殖并诱导其凋亡。DC120在体外和体内均以剂量和时间依赖性方式阻断AKT信号通路中下游分子的磷酸化。然而，出乎意料的是，DC120激活了雷帕霉素复合物1（mTORC1）的哺乳动物靶点，这是由70KD核糖体蛋白S6激酶（P70S6K）和真核翻译起始因子4E结合蛋白1（4E-BP1）磷酸化增加所表明的。mTORC1信号的激活是由于AKT抑制后细胞内Ca(2+)通过Ca(2+)/钙调蛋白（CaM）/信号传导至人液泡蛋白分选34（hVps34）而增加。同时，DC120通过降低CRAF在Ser259处的磷酸化减弱了AKT对CRAF的抑制作用，从而激活了丝裂原活化蛋白激酶（MAPK）通路。DC120对mTORC1和MAPK通路的激活并非相互依赖，并且DC120与mTORC1抑制剂和/或MEK抑制剂联合使用在体外和体内均诱导了显著的细胞凋亡和生长抑制。综上所述，AKT、mTORC1和/或MEK抑制剂联合使用将是一种很有前景的肝癌治疗策略。
