Cytosolic Phospholipase A2 Determines Intercellular Heterogeneity of Stress Granules and Chemotherapy Response

Cancer cell heterogeneity is a major therapeutic challenge. In this study, we identify that individual cells within cancer cell populations show significant heterogeneity in the levels of the stress-adaptive organelles, stress granules (SG), and demonstrate that SG heterogeneity is dictated by the cell cycle state. Specifically, SG formation is distinctively heightened in cells in the G2 phase because of the interplay between a nonapoptotic function of CASPASE-3 and calcium-dependent phospholipase A2 (cPLA2)-mediated production of the SG-promoting molecule, 15-deoxy-delta-prostaglandin-J2. We demonstrate that in the G1-S phase, CASPASE-3 cleaves and inactivates cPLA2, whereas in the G2 phase, CASPASE-3 activity is suppressed, resulting in enhanced cPLA2 activity and 15-deoxy-delta-prostaglandin-J2 upregulation. We show that cell cycle-dependent SG heterogeneity is a property of pancreatic ductal adenocarcinoma and targeting G2-SGs by inhibiting cPLA2 sensitizes pancreatic ductal adenocarcinoma to G2 arrest-inducing chemotherapeutics. Our findings highlight cell cycle-dependent SG formation as a fundamental property of SGs, a key aspect of cancer heterogeneity, and a target for cancer treatment. SIGNIFICANCE: Because of their defective G1 checkpoint mechanisms, cancer cells often activate a G2 checkpoint, which leads to resistance to DNA-damaging chemotherapeutics. We identify an intercellular heterogeneity of SGs that is driven by the cell cycle, with SG formation being highest in the G2 phase. Targeting G2-specific SG formation sensitizes pancreatic tumors to G2 arrest-inducing chemotherapeutics.