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

Abstract

Therapeutic resistance and recurrence are primary contributors to poor outcomes in breast cancer patients.  Induction of ferroptosis, a type of cell death characterized by overload of toxic lipid peroxides has appreciated as a viable strategy in treatment of breast cancers including lethal subtypes such as triple-negative breast cancer (TNBC). Notwithstanding, some cancer subtypes are resistant to ferroptosis and the underlying mechanisms remain incompletely understood. The current study shows that phosphoglycerate kinase 1 (PGK1), a glycolysis-regulating enzyme, is highly expressed in advanced tumor stages, and correlates with ferroptosis resistance as well as poor outcomes, especially in TNBCS.  Using genetic and pharmacological approaches, we demonstrated that PGK1 depletion attenuates ferroptosis resistance in TNBC and luminal breast cancer cell lines. We also showed that PGK1 depletion destabilizes GPX4, an anti-ferroptosis defense peroxidase in parallel with pyruvate dehydrogenase (PDH) to disrupt redox homeostasis and enhance lipid peroxidation.  In orthotopic TNBC models, we showed that tumoral loss of PGK1 enhances activity of the ferroptosis inducer imidazole ketone erastin (IKE) and reduces tumor size and metastasis.  These results indicate that PGK1 plays a key role in modulating breast cancer sensitivity to ferroptosis induction, suggesting that this kinase may be exploited as a therapeutic target to overcome resistance to ferroptosis inducers in breast cancers.