Feedback Loops Blockade Potentiates Antitumor Activity of a Novel AKT1 Inhibitor DC120 in Human Liver Cancer Cells and Nude Mice Xenografts
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 that a novel AKT1 kinase inhibitor,DC 120,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,such as glycogen synthetase kinase-3 beta (GSK3β),human forkhead box (FOX) family numbers and mammalian target of rapamycin (mTOR),in dose-and time-dependent manners.Furthermore,DC 120 enhanced the interaction of AKT and proline-rich AKT substrate of 40KD (PRAS40),which led to the relief of mTOR complex 1 (mTORCI) inhibition by PRAS40 and constitutive activation of the mTORCI pathway.DC120 attenuated the inhibitory effect of AKT on CRAF by decreasing the phosphorylation of CRAF at Ser259 and activated the mitogen-activated protein kinase (MAPK) pathway.The activation of the mTORC1 and MAPK pathways following DC120 treatment were not mutually dependent.The combination of DC120 with an mTORC1 inhibitor or MEK inhibitor induced significant apoptosis and the inhibition of tumor growth,respectively,both in vitro and in vivo.The combination of these three inhibitors synergistically induced apoptosis in liver cancer cells.Conclusion:The novel AKT1 inhibitor DC120 activates the mTORC1 and MAPK pathways,and the blockade of these feedback loops can significantly enhance the antitumor activity of DC 120.These results indicated that a combination of AKT,mTORC1 and/or MEK inhibitors may be a promising therapeutic strategy for liver cancer treatment.
Fen Yang Xiao-Feng Zhu Rong Deng Shao-Hua Chang Xiao-Jun Qian Xiao-Qi Wu Juan Qin Ting Sun Gong-Kan Feng Ke Ding
State Key Laboratory of Oncology in South China,Cancer Center,Sun Yat-Sen University,Guangzhou China Key Laboratory of Regenerative Biology and Institute of Chemical Biology,Guangzhou Institutes of Bio
国内会议
2012医学科学前沿暨第二届个体化治疗与抗肿瘤药物研究新趋向研讨会
深圳
英文
248-272
2012-07-13（万方平台首次上网日期，不代表论文的发表时间）