The thought of killing cancer cells without adverse effects on normal cells is a long held ideal of cancer therapy. This kinase plays a vital role in the intrinsic death pathway and has been shown to phosphorylate and antagonize Bcl xL, Bcl 2, and Mcl 1. Oxaliplatin triggers DNA strand breaks and activation of JNK independently of DNA mismatch repair proteins, despite cisplatin, and subsequent apoptosis that involves PUMA. The precise molecular information on oxaliplatin induced JNK activation are unclear. The recognition of JNK dependent phosphorylation of serine 62 of Bcl xL by El Fajoui et aladds another path by which JNK regulates the mitochondrial demise pathway through the Bcl 2 family and supplies a molecular explanation for oxaliplatin induced sensitization of cancer cells to TRAIL. Integrating this finding Everolimus RAD001 with your oxaliplatin induced cellular events and present understanding of TRAIL, it’s obvious that oxaliplatin induced apoptosis and sensitization to TRAIL is conferred by JNK dependent phosphorylation of Bcl 2 family members. DNA replication is inhibited by oxaliplatin by developing platinum DNA adductsand consequently activates JNK, which phosphorylates the antiapoptotic Bcl 2 household members Bcl xL, Bcl 2, and Mcl 1 to affect their relationships with Bax and Bak to market apoptosis. However, the mobile consequence of initiating JNK is not easily predicted because of the amount of JNK substrates and its apparently contradictory functions in cell survival and cell death that are highly Metastasis context dependent. Within the Bcl 2 family, the net result of JNK activation of Bcl 2 isn’t easy, because JNK can also phosphorylate Bad to suppress apoptosis and Bcl w can prevent activation of JNK. Prosurvival signaling induced by TRAIL can also directly activate JNK, even though practical effect of this seems to be cell type specific, to enhance the complexity. However, this wasn’t seen in HT29 and V9P cells utilized by El Fajoui et alin this study. CTEP The observation that apoptosis induced by oxaliplatin and TRAIL is dependent on caspase 9 and independent of caspase 8 is fascinating as caspase 8 plays an initiator role in both type I and type II canonical signaling pathways of TRAIL. Type II cells are expected to be dependent on caspase 9, since the zymogen is activated by being a essential effector the apoptosome to initiate the caspase cascade. But, it has been previously mentioned that TRAIL induced cell death may be triggered independently of caspase 8. We’ve previously found that caspase 9 may play a vital role in the sensitivity of typical hepatocytes and esophageal epithelial cells to TRAIL, while cancer cells seem to depend on caspase 8. The molecular information on caspase 8 independent cell death signaling by TRAIL and the determinants of the bifurcation of signaling events after caspase 8 activation between type I and type II cells remain unclear.