J Cancer 2018; 9(6):987-997. doi:10.7150/jca.22861

Research Paper

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

Ning Wu1✉*, Yingfeng Zhu2*, Xiao Xu3*, Yongjun Zhu1, Yang Song1, Liewen Pang1, Zhiming Chen1✉

1. Department of Cardio-thoracic Surgery, HuaShan Hospital of Fudan University, Shanghai, 200040, China.
2. Department of Pathology, HuaShan Hospital of Fudan University, Shanghai, 200040, China.
3. Central laboratory, HuaShan Hospital of Fudan University, Shanghai, 200040, China.
*These authors contributed equally to this work.

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.

Keywords: Esophageal squamous cell carcinoma, PI3K/mTOR inhibitor, Histone deacetylase inhibitor, angiogenesis, Prognosis.

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How to cite this article:
Wu N, Zhu Y, Xu X, Zhu Y, Song Y, Pang L, Chen Z. The anti-tumor effects of dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A on inducing autophagy in esophageal squamous cell carcinoma. J Cancer 2018; 9(6):987-997. doi:10.7150/jca.22861. Available from http://www.jcancer.org/v09p0987.htm