Effect of Her-2/neu Signaling on Sensitivity to TRAIL in Prostate Cancer
Annaul rept. 1 Jun 2004-31 May 2005
PITTSBURGH UNIV PA
Pagination or Media Count:
Tumor necrosis factor-related apoptosis-inducing ligand TRAIL has been shown to be selective in the induction of apoptosis in cancer cells with minimal toxicity to normal tissues. However, not all cancers are sensitive to TRAIL- mediated apoptosis. Thus, TRAIL-resistant cancer cells must be sensitized first to become responsive to TRAIL. In this study, we observed that pretreatment of acetyl salicylic acid ASA augmented TRAIL-induced apoptotic death in human prostate adenocarcinoma LNCaP and human colorectal carcinoma CX-1 cells. Western blot analysis showed that pretreatment of ASA followed by TRAIL treatment activated caspases 8, 9, and 3 and cleaved PARP poly ADP-ribose polymerase, the hallmark feature of apoptosis. Interestingly, at least 12 h of pretreatment with ASA was prerequisite for promoting TRAlL-induced apoptosis and was related to downregulation of Bcl-2. Biochemical analysis revealed that ASA inhibited NF- B activity, which is known to regulate Bcl-2 gene expression, by dephosphorylating I B- and inhibiting IKK activity, but not by affecting the HER-2-PI3K-Akt signal pathway. Overexpression of Bcl-2 suppressed the promotive effect of ASA on TRAIL-induced apoptosis and changes in mitochondrial memembrane potential. Taken together, our studies suggest that ASA-promoted TRAIL cytotoxicity is mediated through downregulating Bcl-2 and decreasing mitochondrial membrane potential.
- Medicine and Medical Research