Cystathionine β-synthase Induces Multidrug Resistance and Metastasis in Hepatocellular Carcinoma

Objective: This study aims to analyze whether Cystathionine β-synthase (CBS) plays roles in hepatocellular carcinoma (HCC) drug resistance. Methods: MTS assay was used to detect the effect of chemotherapeutic drugs doxorubicin (DOX) and sunitinib on HCC cell viability and cell growth. Intracellular doxorubicin accumulation assay was performed to evaluate the sensitivity of DOX and sunitinib in HCC cells and the function of multidrug resistance-associated protein Pglycoprotein (P-gp). Quantification of H2S production was performed using the methylene blue method. Production of intracellular ROS was quantified using the DCFHDA assay. The scratch wound and transwell assays were used to determine the cell migration and invasion. Expression of proteins was tested by western blot analysis. Results: HepG2 cells with high CBS expression were less sensitive to DOX and sunitinib and knockdown of CBS significantly elevated the sensitivity to DOX and sunitinib in HepG2 cells. In contrast, CBS overexpression increased the resistance of DOX and sunitinib in BEL-7404 cells. Moreover, the overexpression of CBS caused the up-regulation of the expression level of P-gp and the decrease of DOX accumulation in BEL-7404 cells. In further mechanism research, we found that STAT3/Akt/Bcl-2 pathway activation, reactive oxygen species (ROS) inhibition as well as enhancement of the metastatic ability of hepatoma cells were responsible for the HCC drug resistance. Conclusion: CBS overexpression conferred HCC cell resistance. Keywords: Cystathionine β-synthase, multidrug resistance, metastasis, hepatocellular carcinoma, DOX, GST.