SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Sodium-glucose transporter 2 (SGLT2) inhibitors are approved for type 2 diabetes.
• Emerging evidence suggests SGLT2 inhibitors possess anti-cancer properties against various cancer cells.
• The precise mechanisms underlying SGLT2 inhibitor efficacy in cancer remain under investigation.

Purpose of the Study:

• To investigate the anti-cancer effects of SGLT2 inhibitors on colorectal cancer (CRC) cells.
• To elucidate the molecular mechanisms, including metabolic alterations and cell death pathways, involved in SGLT2 inhibitor-induced CRC cell growth inhibition.
• To identify potential molecular targets and pathways modulated by SGLT2 inhibitors in CRC.

Main Methods:

• Quantitative real-time PCR and western blot to determine SGLT2 expression in CRC cell lines.
• Cell Counting Kit-8 (CCK-8) assays to assess cell proliferation.
• XF HS Seahorse Bioanalyzer and flow cytometry to evaluate cellular metabolism, energy production, and apoptosis.
• Transient gene silencing and protein-protein interaction network analysis to identify SGLT2 molecular targets.

Main Results:

• SGLT2 inhibitors induced cell cycle arrest, impaired glucose and energy metabolism, and promoted apoptosis and ER stress-induced autophagy in CRC cells.
• These effects were associated with the upregulation of sirtuin 3 (SIRT3).
• SIRT3 silencing attenuated the metabolic and apoptotic effects of SGLT2 inhibitors, and dipeptidyl peptidase 4 (DPP4) was identified as a potential common target.

Conclusions:

• SGLT2 inhibitors demonstrate significant anti-tumor activity against colorectal cancer cells.
• The SGLT2/SIRT3 axis plays a crucial role in the cytotoxic mechanisms of SGLT2 inhibitors in CRC.
• These findings highlight the potential of SGLT2 inhibitors as a therapeutic strategy for colorectal cancer.