G2A as a key modulator of carbonyl stress and apoptosis resistance in glucose-loaded cancer cells

Cancer cells exhibit high glycolytic activity, metabolizing glucose as their primary energy substrate. Toxic metabolites produced during glycolysis, such as methylglyoxal, induce carbonyl stress (CS), promoting inflammation and oxidative stress. The elevated glucose metabolism in cancer cells creates this toxic environment. However, little research has focused on the molecules mediating these reactions and stresses, and their role in selecting and enriching apoptosis-resistant cells. This study investigated the impact of constitutively suppressing oxidized lipid receptor G2A (GPR132) expression on the relationship between CS and oxidative stress in glucose-loaded cancer cells. G2A has recently attracted attention as a tumor promoter. However, our study shows that G2A suppression under glucose loading significantly reduces CS and associated oxidative stress, thereby enhancing cancer cell survival. This suggests a new mechanism contrary to conventional thinking, involving the acute induction of glyoxalase 1 (Glo1). G2A may thus play a role in selecting and enriching apoptosis-resistant cell populations under high glucose conditions by regulating Glo1 expression. These findings improve our understanding of the adaptive capacity of cancer cells to glucose toxicity. •G2A suppression reduces carbonyl and oxidative stress of glucose-loaded cancer cells.•Constitutive inhibition of G2A expression leads to enhanced Glo1 activity.•G2A acts as a mediator in the interaction between carbonyl and oxidative stress.•G2A suppression aids in the adaptation of cancer cells to glucose toxicity.•G2A targeting is a potential strategy to manage cancer resistance in high glucose.