NOXA the BCL-2 Family Member behind the Scenes in Cancer Treatment

Abstract

Apoptosis, a programmed cell death relying on the cascade activation of caspases, regulates many processes ranging from embryonic development to immune homeostasis, and plays a major role in cancer. Escape from apoptosis is indeed one of the fundamental characteristics of tumor cells that frequently exhibit increased expression of the main prosurvival BCL-2 homologues BCL-2, BCL-xL and/ or MCL-1 contributing to tumor progression or resistance to anticancer treatments [1]. Mitochondria Outer Membrane Permeabilization (MOMP) is a key cellular event in apoptosis as subsequent release of cytochrome-c (cyto-c) from the mitochondrial intermembrane space to cytosol through BAX/BAK pores, promotes apoptosome formation and downstream activation of apoptotic effector caspases. MOMP can also lead to the release of other mitochondrial components including mitochondrial DNA that engage additional inflammatory signalling pathways inhibited by apoptotic caspases [2,3]. BCL-2 family proteins tightly control BAX/BAK-dependent MOM permeability through a dynamic network of protein-protein interactions integrating various cellular stresses and finally dictating life or death decisions and cell fates [4]. Chemotherapies often upregulate expression of proapoptotic BCL-2 homologues in cancer cells, shifting by this way the balanced death/survival signals towards apoptosis as an expected cytotoxic effect. Among the proapoptotic BH3only proteins of the BCL-2 family, NOXA is unique since in preferentially inhibiting the prosurvival BCL-2 homologue MCL-1, it decreases the protective effect MCL-1 exerts on mitochondrial membranes and transfers MOM integrity surveillance and downstream prevention of caspase activation, mostly to BCL-2 and/or BCL-xL. This was observed in particular during mitotic-related stress after antimitotic treatment or during endoplasmic reticulum (ER) stress induced by proteasome inhibitors, where NOXA was shown to accumulate through transcriptional or post-translational mechanisms, as we detail in this review. Importantly, prosurvival members of BCL-2 family are Abstract