RIPK1-Dependent Mitophagy: A Novel Mechanism to Eliminate ECM-Detached Cells

<p>For cancer cells to survive during extracellular matrix (ECM) detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to reactive oxygen species (ROS) generation, although the mechanistic underpinnings of this link remain ill defined. Here, we uncover a role for receptor-interacting protein kinase 1 (RIPK1) in the modulation of mitochondrial ROS levels and cell viability during ECM detachment. Mechanistically, we find that RIPK1 activation during ECM detachment results in the induction of mitophagy through a mechanism requiring the mitochondrial phosphatase phosphoglycerate mutase family member 5 (PGAM5). As a consequence of mitophagy induction, ECM-detached cells experience diminished isocitrate dehydrogenase 2 (IDH2)-mediated nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) production in the mitochondria and the subsequent elevation in mitochondrial ROS levels leads to non-apoptotic cell death. Furthermore, we find that antagonizing RIPK1 or PGAM5 enhances tumor formation <i>in vivo</i>. Expanding upon these studies further, we also find that prostate cancer cell lines that have developed resistance to the immune checkpoint blockade inhibitor PD-1 have antagonized the liability associated with RIPK1/PGAM5-dependent mitophagy to enhance survival during ECM detachment. In aggregate, RIPK1-mediated induction of mitophagy may be an efficacious target for therapeutics aimed at eliminating ECM-detached cancer cells. </p>