Expression of PGK1 in Breast Cancers Alters Their Sensitivity to Ferroptosis Induction via Metabolic Reprogramming

Abstract Therapeutic resistance and recurrence are among the major contributors to poor outcomes for patients with breast cancer. Induction of ferroptosis, a form of cellular death characterized by toxic lipid peroxide overload, has emerged as a promising therapeutic strategy against breast cancers including triple-negative breast cancer(TNBC). Nevertheless, certain types of cancer are impervious to induction of ferroptosis and the underlying mechanisms remain incompletely clear. In this study, we show that phosphoglycerate kinase 1 (PGK1), an important enzyme in glycolysis, is highly expressed in breast tumors, and the elevated levels of PKG expression correlate with advanced tumor stages, poor prognosis and ferroptosis insensitivity, particularly in TNBCs. Using genetic or pharmacological inhibition, we demonstrate that knockdown or inhibition of PGK1 enhances ferroptosis sensitivity in both TNBC and luminal breast cancer cell lines. We further demonstrate that depletion of PGK1 destabilizes glutathione peroxidase 4 (GPX4), an anti-ferroptotic defense peroxidase, thereby disturbing cellular redox homeostasis and promoting lipid peroxidation. Moreover, targeting PGK1 disrupts glycolytic metabolism and sensitizes breast cancer cells to ferroptosis induction in tumor cells subjected to glucose deprivation or treated with glycolytic inhibitors. In orthotopic TNBC models, loss of tumoral PGK1 augments the action of the ferroptosis inducer, imidazole ketone erastin (IKE), in inhibiting tumor growth and metastasis, and enhances CD8 + T cell-mediated anti-tumor immunity. These results indicate that PGK1 has a critical role in modulating breast cancer invulnerability to induction of ferroptosis, implying that this kinase may be exploited as a therapeutic target to sensitize breast cancers, especially, TNBC, to ferroptosis inducers.