Dual Effect of Combined Metformin and 2-Deoxy-D-Glucose Treatment on Mitochondrial Biogenesis and PD-L1 Expression in...

Area of Science:

• Oncology
• Metabolic pathways
• Immunology

Background:

• Metformin and 2-deoxy-D-glucose (2DG) show anti-cancer effects, including suppressed proliferation and PD-L1 expression.
• These agents can induce triple-negative breast cancer (TNBC) cell detachment, but their impact on mitochondria is unknown.

Purpose of the Study:

• To investigate the effects of metformin, 2DG, and their combination on TNBC cell mitochondria in vitro.
• To explore the impact on mitochondrial biogenesis, mitophagy, and the unfolded protein response.
• To assess the combined effects on PD-L1 and PD-1 expression in cancer and immune cells.

Main Methods:

• In vitro analysis of metformin, 2DG, and metformin + 2DG on TNBC cell mitochondria.
• Evaluation of mitochondrial mass, size, number, and morphology.
• Assessment of mitochondrial biogenesis, mitophagy, and the unfolded protein response (UPR).
• Analysis of N-glycosylation, PD-L1 surface expression, and PD-1 expression in Jurkat cells.

Main Results:

• Metformin + 2DG significantly increased mitochondrial mass in TNBC cells, primarily through enhanced mitochondrial biogenesis.
• 2DG and metformin + 2DG induced the unfolded protein response by inhibiting N-glycosylation, contributing to mitochondrial enlargement.
• These drugs reduced PD-L1 surface expression on MDA-MB-231 cells and PD-1 expression on Jurkat cells, while largely preserving cytokine secretion.

Conclusions:

• Metformin and 2DG increase mitochondrial mass in TNBC cells via enhanced biogenesis.
• The combination therapy inhibits N-glycosylation, potentially triggering mitochondrial enlargement and reducing PD-L1 expression.
• Metformin and 2DG show promise as adjunct therapies to enhance anti-tumor immunity in TNBC.