Inhibition of β-glucosidase overcomes gastric cancer chemoresistance through inducing lysosomal dysfunction

Abstract

The clinical management of gastric cancer still remains challenge due to its poor response to chemotherapy. Better understanding the underlying mechanisms is required for the identification of more comprehensive therapies to overcome chemoresistance in gastric cancer. GBA1 level was systematically analyzed in gastric cancer patients before and after chemotherapy, and gastric cancer cells exposed to long-term chemo agent's treatment. The roles of GBA1 and its downstream mechanisms were investigated using pharmacological and genetic approaches. We observed the time-dependent upregulation of GBA1 expression and enzyme activity in multiple gastric cancer cell lines in response to prolonged exposure of 5-FU. It is noted that this phenomenon was also observed in gastric cancer patients after chemotherapy. Interestingly, no significant differences on GBA1 expression were detected between normal and malignant gastric tissues. These suggest that the predominant role of GBA1 is in the development of gastric cancer chemoresistance rather than tumorigenesis. Functional analysis demonstrated that GBA1 inhibition suppressed gastric cancer growth and survival without affecting migration, and augmented 5-FU's efficacy. Consistently, GBA1 inhibition was active against 5-FU-resistant gastric cancer cells. Mechanism studies showed that GBA1 inhibition led to loss of lysosomal integrity and function in 5-FU-resistant gastric cancer cells. We are the first to show that inhibition of β-glucosidase (encoded by GBA1) sensitizes gastric cancer to chemotherapy. Our findings demonstrate the therapeutic value of inhibiting GBA1 in gastric cancer, particularly in those who develop chemoresistance.