Celecoxib sensitizes gastric cancer to rapamycin via inhibition of the Cbl-b-regulated PI3K/Akt pathway

Mammalian target of rapamycin (mTOR) has emerged as a new potential therapeutic target for gastric cancer. However, a phase III clinical trial found that monotherapy with the mTOR inhibitor everolimus did not significantly improve the overall survival of patients with advanced gastric cancer. This has led to the exploration of more effective combinatorial regimens to enhance the effectiveness of mTOR inhibitors. Here, we demonstrate that Akt phosphorylation is increased in the rapamycin-resistant gastric cancer cell lines MGC803 and SGC7901. We further show that combined treatment with celecoxib and rapamycin results in an additive inhibitory effect on the growth of gastric cancer cells through suppression of rapamycin-induced Akt activation. Moreover, celecoxib upregulated the expression of the ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b). Knockdown of Cbl-b significantly attenuated celecoxib-mediated inhibition of Akt phosphorylation and impaired the additive anticancer effect of celecoxib and rapamycin. Our results suggest that celecoxib-mediated upregulation of Cbl-b is responsible, at least in part, for the additive antitumor effect of celecoxib and rapamycin via inhibition of rapamycin-induced Akt activation.