An SGLT2 inhibitor modulates SHH expression by activating AMPK to inhibit the migration and induce the apoptosis of cervical carcinoma cells

Abstract

In addition to their hypoglycemic effect, sodium-glucose cotransporter 2 (SGLT2) inhibitors have many other benefits. In the present study, we examine the anticancer effect of the SGLT2 inhibitor empagliflozin using cervical carcinoma models. In vivo antitumor activities of empagliflozin were observed in a nude mouse model. Empagliflozin intervention and downregulation of Sonic Hedgehog Signaling Molecule (Shh) inhibited the migration and promoted the apoptosis of cervical cancer cells in nude mice. Compared with the control group, the empagliflozin treatment group had an increased level of AMP-activated protein kinase (AMPK) and decreased levels of Forkhead Box A1 (FOXA1) and SHH in tumor tissue. In vitro experiments also showed that empagliflozin (50μM) inhibited the migration of cervical cancer cells and induced their apoptosis by activating the AMPK/FOXA1 pathway and inhibiting the expression of SHH. Kaplan-Meier survival analysis was used to determine the relationship between SHH expression and total survival time. The results showed that in cervical cancer patients, high SHH expression resulted in unfavorable overall survival. The downregulation of SHH with small interfering RNA (siRNA) inhibited the migration and invasion and promoted the apoptosis of HeLa cells. These findings show that empagliflozin has a potential therapeutic effect on cervical cancer. This effect was related to the activation of the AMPK pathway and the inhibition of SHH expression.