NOXA/MCL-1 axis determines cell-death decision between apoptosis and a GSDME-dependent cell death associated with production of inflammatory cytokines upon treatment of breast cancer cells with antimitotics.

Understanding how malignant cells respond to chemotherapy is essential to prevent the development of resistance and to improve the efficiency of anticancer drugs. Antimitotic treatment in breast cancer cells increases NOXA, an endogenous inhibitor of the survival protein MCL-1. We herein show that whereas the extent of cell death is determined by the compensatory survival BCL-xL, NOXA/MCL-1 balance determines the modality of cell death demise. Indeed, genetic inactivation of NOXA, which reinforces the pro-survival function of MCL-1 in cancer cells, only postpones death upon exposure to Taxol and BCL-xL antagonism with A1331852. It directs the morphology of dying cells towards a phenotype characterized by cell swelling and balloon-like bubbling, regulated by Caspase-3 and GSDME, indicating that NOXA and MCL-1 might function as negative and positive, respectively, regulators of this cell death mode. Importantly, a comparative analysis of secretomes from NOXA-proficient and NOXA-deficient cancer cells treated with Taxol revealed variations in the production of inflammatory cytokines, including IL-1α, IL-1β, and IL-18. Thus, induction of apoptosis or a vacuole-associated and inflammatory cell death, in breast cancer cells by antimitotic treatment, relies on pore-forming protein GSDME expression but also on a fine balance within the BCL2 family network.