The Death Receptor 5 regulates 5-FU-induced apoptosis via the p38 SAPK pathway

Apoptosis is an important process that helps to eliminate damaged or unwanted cells, including cancer cells during chemotherapy treatment. Previous work identified a novel apoptosis-inducing complex and pathway that is triggered by the chemotherapeutic drug 5FU. 5FU causes DNA damage that gives rise to the activation of ATR and subsequent upregulation of caspase-10, which in turn recruits FADD, caspase-8, TRAF2 and RIP1 to a complex termed FADDosome. Within the FADDosome caspase-8 is activated leading to downstream apoptosis signalling via Bid and mitochondria. Interestingly, 5FU induced apoptosis is lower in p53 knock-out cells without affecting the FADDosome-mediated caspase-8 activation. Therefore, this study investigates the role of p53 and the molecular pathways it controls in 5FU-induced apoptosis in colorectal cancer cells. I found that 5-FU regulates FADDosome-induced apoptosis through p53-dependent upregulation of TRAILreceptor 2 (TRAIL-R2) also known as Death Receptor 5 (DR5), leading to a partial activation of the receptor independent of its ligand TRAIL. This activation triggers non-canonical signalling including the p38 MAPK pathway, which is absent or substantially reduced in p53-null and DR5 knock-down cells. Co-treatment of cells with 5-FU and p38 inhibitors diminished apoptosis levels by about 50%. These results demonstrate that the role of p53 in chemotherapy-induced apoptosis is more complex and potentially more multi-facetted than expected. TRAIL-R2 activated p38 MAPK might promote the activation of Bid by active caspase-8 or other molecular mechanisms that lead to mitochondrial outer membrane permeabilization (MOMP). As MOMP is needed for the release of Smac/Diablo from the mitochondria to inhibit the anti-apoptotic protein XIAP, this mechanism is essential for the full execution of apoptosis, and can explain the relative resistance in p53-null cells.