| Mammalian target of rapamycin (mTOR) is aberrantly activated in hepatocellular carcinoma (HCC) and plays pivotal roles in tumorigenesis and chemoresistance. Rapamycin has been reported to exert anti-tumor activity in HCC and sensitizes HCC cells to cytotoxic agents. However, due to feedback activation of AKT after mTOR complex1(mTORC1) inhibition, simultaneous targeting of mTORCl/2may be more effective.In this study, we examined the interaction between the dual mTORCl/2inhibitor OSI-027and doxorubicin in vitro and in vivo. OSI-027was found to reduce phosphorylation of both mTORC1and mTORC2substrates, including4E-BP1, p70S6K and AKT (Ser473), and inhibit HCC cell proliferation. Similar to OSI-027treatment, knockdown of mTORC2induced G0/G1phase cell cycle arrest. In contrast, rapamycin or knockdown of mTORC1increased phosphorylation of AKT (Ser473), yet had little antiproliferative effect. Notably, OSI-027synergized with doxorubicin for the antiproliferative efficacy in a manner dependent of MDR1expression in HCC cells. The synergistic anti-tumor effect of OSI-027and doxorubicin was also observed in a HCC xenograft mouse model. Moreover, AKT was required for OSI-027-induced cell cycle arrest and downregulation of MDR1. Our findings provide a rationale for dual mTORC1/mTORC2inhibitors, such as OSI-027, as monotherapy or in combination with cytotoxic agents to treat HCC. |
