Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway

Colorectal cancer is the third most frequently diagnosed malignancies among both men and women, which has an increased mortality but a poor prognosis. Targeting mTOR becomes an effective approach that shows promising antitumor activities in various cancers including colonic carcinoma. However, the potential mechanism against colon cancer remains incompletely understood. Here, we demonstrated that the anti-cancer effect of AZD8055 and OSI-027 is at least in part modulated by the gradual process of apoptosis initiation, progressing from mTOR suppression, 4EBP1 dephosphorylation, or EZH2 suppression, thereby leading to PUMA-dependent apoptosis via the intrinsic mitochondrial pathway. Furthermore, AZD8055 inhibited colorectal cancer tumor growth in mice significantly. PUMA deletion caused resistance of dual mTOR inhibitors, suggesting PUMA mediated carcinogenesis in vitro and in vivo. Collectively, these findings established a vital status of PUMA in driving the antineoplastic efficacy of targeting mTOR by AZD8055 and OSI-027 and offered the rationales for the current clinical assessment.