Tumor glucose reprogramming suppresses cuproptosis: A review

Area of Science:

• Molecular Biology
• Cancer Research
• Metabolic Pathways

Background:

• Cuproptosis is a copper-dependent regulated cell death pathway initiated by FDX1-mediated reduction of Cu²⁺ to Cu¹⁺.
• Copper ions bind lipoylated enzymes in the TCA cycle, leading to protein aggregation and proteotoxic stress.
• Tumors often evade cuproptosis via glucose metabolism alterations, including HIF-1α and MYC-driven PDK activation.

Purpose of the Study:

• To elucidate the mechanisms by which cancer cells evade copper-dependent cell death (cuproptosis).
• To identify key metabolic pathways and regulators involved in conferring resistance to cuproptosis.
• To propose novel therapeutic strategies targeting metabolic vulnerabilities in cancer.

Main Methods:

• Analysis of metabolic rewiring in cancer cells, focusing on the TCA cycle, glycolysis, and PPP.
• Investigation of gene expression changes related to cuproptosis, including FDX1, GLS, and PDC subunits.
• Correlation of clinical data with metabolic markers (PDK, PDC) to assess prognostic significance.

Main Results:

• Glycolytic reprogramming, including increased PDK activity and suppressed FDX1, reduces sensitivity to cuproptosis.
• Pentose Phosphate Pathway (PPP) and glutaminolysis generate NADPH and GSH, which chelate copper and quench ROS.
• High PDK and low PDC expression correlate with poor prognosis in cancer patients, indicating metabolic adaptation.

Conclusions:

• Cancer cells exploit metabolic pathways to evade copper-induced cell death, presenting a therapeutic vulnerability.
• Combination therapies involving PDK inhibitors, PPP/GLS pathway modulation, and copper ionophores show promise.
• Further research into FDX1 regulation and crosstalk with other cell death pathways is crucial for clinical translation.