Abstract 5840: Inhibition of cystathionine-β-synthase (CBS) sensitizes colon cancer cells to 5-FU via increasing apoptosis and inhibiting cellular bioenergetics

Abstract

Abstract Increased expression of cystathionine-β-synthase (CBS) has been validated in multiple kinds of tumor tissues, including colorectal cancer. Endogenous hydrogen sulfide (H2S), produced by CBS, was able to promote the proliferation and migration of colon cancer cells by inhibiting apoptosis and injuries caused by noxious environmental factors, including chemotherapeutic agents. Recently, overexpression of CBS has been reported to play a pivotal role in tumorigenesis of colon cancer cells, rendering the normal colon epithelial cell line acquiring the features of malignant cells. However, the potential role of CBS in the development of chemoresistance of colon cancer cells has not be illustrated. In the present study, overexpression of CBS in tumor tissues was further validated by realtime PCR and the effect of inhibition of both the activity and expression of CBS on the sensitivity to 5-fluorouracil (5-FU) was investigated in colon cancer cell lines. Inhibition of the activity of CBS by CBS inhibitor aminooxyacetate (AOAA) significantly increased the sensitivity of colon cancer cell lines to 5-FU, featured by decreased IC50 and colony forming efficiency. However, utilizing a slowly releasing H2S donor GYY4137, the present study suggested that exogenous hydrogen sulfide was able to increase the resistance to 5-FU in both colon cancer cell lines. What's intriguing was that, 5-FU, at clinically relevant concentrations, significantly inhibited the expression of CBS. Co-treatment of AOAA significantly increased the expression of Bax and decreased the expression of Bcl-2, indicating the involvement of increased apoptosis. AOAA also predisposed the colon cancer cells to the inhibition of cellular energetics induced by 5-FU, featured by the further reduced level of cellular ATP. These results suggested that inhibition of CBS promoted the sensitivity of colon cancer cells to 5-FU via increasing apoptosis and inhibiting cellular bioenergetics. Furthermore, inhibition of CBS expression by shRNA sensitizes the 5-FU resistant colon cancer cell line HCT-8/5-FU to treatment with 5-FU. The increased expression of CBS and the consequently increased level of endogenous H2S might be a potential therapeutic target for chemoresistance in colon cancer. Citation Format: Shanwen Chen, Pengyuan Wang, Yisheng Pan, Yucun Liu. Inhibition of cystathionine-β-synthase (CBS) sensitizes colon cancer cells to 5-FU via increasing apoptosis and inhibiting cellular bioenergetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5840.