The anti-tumor effects of dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A on inducing autophagy in esophageal squamous cell carcinoma.

Abstract

The effect and regulation of autophagy-related proteins Beclin-1 and LC3 in esophageal squamous cell carcinoma have not been fully studied. The aim of this study was to assess the expression of Beclin-1 and LC3 in ESCCs, and to investigate the association between the two markers and clinicopathological characteristics as well as prognosis. Meanwhile, we explored the anti-tumor effect of the PI3K/mTOR dual inhibitor BEZ235 and the histone deacetylase inhibitor TSA on inducing autophagy in ESCC cells. Our study included 118 ESCC tumors and paired non-tumor esophageal mucosa tissues. Beclin-1 and LC3 expression were performed by immunohistochemistry. Human ESCC cells Eca-109 and TE-1 were treated with BEZ235 and TSA either alone or in combination in Vitro. The expression of both Beclin-1 and LC3 proteins were decreased significantly in ESCCs, but there was no significant relation between the expression of Beclin-1 and LC3 (P = 0.427). The negative expression of either Beclin-1 or LC3 was associated with advanced TNM stages (P = 0.006 and P<0.001, respectively). Patients with a high expression of Beclin-1 and LC3 predict better prognosis. In Vitro co-treatment with BEZ235 and TSA showed a synergistic effect on inhibition of ESCC cell viability and induction of autophagy with the increasing expressions of Beclin-1, LC3-II and the ratio of LC3-II/LC3-I. Our results demonstrated that the autophagy-related proteins Beclin-1 and LC3 were decreased in ESCCs and the low expression of the two markers predicted a worse prognosis. The co-treatment of BEZ235 and TSA significantly induced autophagy and enhanced anti-tumor activities, provided a new effective therapeutic target in ESCCs.