SGLT2i delays c-Myc-induced HCC progression via targeting mTOR

Background

Hepatocellular carcinoma (HCC) stands as a primary malignant liver tumor characterized by metabolic reprogramming. The oncogene c-Myc exerts substantial influence by driving the transcription of numerous genes. Empagliflozin (EMPA), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), is widely used in the treatment of type 2 diabetes and has recently attracted attention for its potential anti-cancer effects. This study aims to unravel the complex interplay among c-Myc, EMPA, and the mammalian target of rapamycin (mTOR) in HCC development and progression.

Methods

HCC induction in mice utilized high-pressure hydrodynamic transfection of the c-Myc plasmid. QPCR and immunohistochemistry experiments were performed to detect the expression of SGLT2 in HCC tissues. In vivo experiments were conducted to corroborate the upregulation of SGLT2 following c-Myc transfection. In invo and vitro investigations were conducted to evaluate the anti-cancer effects of two SGLT2i: EMPA and canagliflozin (CANA). Network pharmacology, molecular docking analyses, CETSA experiments, and additional western blot experiments were used to reveal EMPA's interaction inhibition with mTOR.

Results

The study identified an increase in SGLT2 expression in HCC tissues as a result of c-Myc overexpression. In vitro experiments confirmed the upregulation of SGLT2 following c-Myc transfection. Notably, the administration of SGLT2i effectively curtailed liver cancer progression, and reduced hepatic fat accumulation in mice. EMPA exhibited significant suppression of cell proliferation in c-Myc-transfected cells. In vitro experiments unveiled EMPA's interaction and with inhibition the activation of mTOR.

Conclusion

Our study highlights EMPA's potential as a therapeutic agent in delaying the development and progression of HCC.