Novel PI3K/Akt/mTOR signaling inhibitor, W922, prevents colorectal cancer growth via the regulation of autophagy.

ABSTRACT

W922, a novel PI3K/Akt/mTOR pathway inhibitor, exhibits efficient anti­tumor effects on HCT116, MCF­7 and A549 human cancer cells compared with other synthesized compounds. The present study aimed to investigate its anti­tumor effects on colorectal cancer cells. A total, of seven different colorectal cell lines were selected to test the anti­proliferation profile of W922, and HCT116 was found to be the most sensitive cell line to the drug treatment. W922 inhibited HCT116 cell viability and cell proliferation in vitro in concentration­ and time­dependent manners. Furthermore, W922 suppressed the tumor growth in a xenograft mouse model and exhibited low toxicity. The proteomic alterations in W922­treated HCT116 cells were found to be associated with cell cycle arrest, negative regulation of signal transduction and lysosome­related processes. W922 caused cell cycle arrest of HCT116 cells in G0­G1 phase, but only triggered slight apoptosis. In addition, the PI3K/Akt/mTOR signaling proteins were dephosphorylated upon W922 treatment. It has been reported that inhibition of mTOR is relevant to autophagy, and the present results also indicated that W922 was involved in autophagy induction. An autophagy inhibitor, chloroquine, was used to co­treat HCT116 cells with W922, and it was identified that the cell cycle arrest was impaired. Moreover, co­treatment of W922 and chloroquine led to a significant population of apoptotic cells, thus providing a promising therapeutic strategy for colorectal cancer.