Oxaliplatin Uses JNK to Restore TRAIL Sensitivity in Cancer Cells Through Bcl-xL Inactivation  Joshua E. Allen, Wafik S. El-Deiry  Gastroenterology  Volume 141, Issue 2, Pages 430-434 (August 2011) DOI: 10.1053/j.gastro.2011.06.026 Copyright © 2011 AGA Institute Terms and Conditions

Figure 1 Oxaliplatin-induced JNK activation overlaps with the TRAIL-mediated intrinsic death pathway. TRAIL initiates cell death by binding proapoptotic death receptors DR4 or DR5 that colocalizes their intracellular death domains. This clustering recruits the Fas-associated death domain (FADD) and pro-caspase-8 that results in its activation through autocatalytic cleavage. In type II cells, active caspase-8 cleaves Bid to a truncated form, tBID, which subsequently interacts with proapoptotic Bcl-2 family members Bax and Bak. This interaction leads to permeabilization of the mitochondrial membrane and release of cytochrome c. Cytosolic cytochrome c then combines with Apaf-1 and ATP to form the apoptosome that activates caspase-9 to trigger apoptosis through the caspase cascade. Oxaliplatin complexes with DNA to form adducts that inhibit DNA replication and therefore induces cellular stress responses. As a consequence, JNK is activated and phosphorylates antiapoptotic Bcl-2 family members such as Bcl-xL at serine 62. This results in dissociation of these proteins with the proapoptotic Bcl-2 family members Bax and Bak. These previously sequestered proteins are now free to oligomerize and porate the mitochondrial membrane to induce apoptosis. Gastroenterology 2011 141, 430-434DOI: (10.1053/j.gastro.2011.06.026) Copyright © 2011 AGA Institute Terms and Conditions