Activation of a Novel Death Pathway, Targeted Necrosis, by p53 Peptides to Circumvent Apoptotic Resistance in Prostate Cancer

摘要

Virtually all chemotherapy agents, at clinically achievable concentrations, act by inducing cancer cell death via apoptosis, but cancer cells eventually become resistant to apoptosis-inducing therapeutic agents. Necrosis, with fewer mechanisms of resistance, might be exploited specifically against prostate cancer cells by induction of 'targeted necrosis'. Targeted necrosis has potential clinical utility, since its cell death mechanism retains the cancer cell specificity of apoptosis and bypasses apoptotic resistance by re-direction into necrosis. Previous studies found that p53p-Ant, a p53 C- terminal peptide fused at its C-terminus to the carrier peptide of antennapedia, induced rapid apoptosis via activation of the Fas/FADD/caspase-8 pathway. In these studies we found synergistic targeted necrosis in prostate cancer cells pre-incubated with paclitaxel, after treatment with p53p-Ant. Paclitaxel treatment alone induced transcription (RT-PCR) and translation (western blotting) of Fas ligand. Addition of dominant negative FADD enhanced necrosis by p53p-Ant, but repressed the synergistic activity with paclitaxel, suggesting the involvement of FAS/FADD pathway. Previous studies indicated that p53p-Ant activates the Fas receptor by flipping the receptor in the extracellular membrane making it available for activation by ligand. Therefore, pretreatment with paclitaxel may prime the cells by induction of Fas ligand so that subsequent exposure to p53p-Ant efficiently activates the Fas/FADD cell death pathway.