Abstract A77: Hydrostatic pressure sensitizes TRAIL‐mediated apoptosis through activating mitochondrial pathway in H460, lung carcinoma cell

TRAIL (tumor necrosis factor related apoptosis inducing ligand) is a member of the TNF superfamily and one of the promising anticancer drugs with high specificity for cancer cells. Accumulating preclinical studies demonstrate that the TRAIL can effectively induce the apoptosis of tumor or transformed cells, but not normal cells; hence, promoting the development of TRAIL‐based cancer therapy. Recent studies for strategy of enhancement of the TRAIL‐mediated apoptosis have been investigated for improving typical cancer therapy by combining treatment with other chemo‐ or radiation and small molecules. Environmental stimuli such as physiological or mechanical conditions can influence the proliferation, differentiation, apoptosis and premature senescence through activating critical signaling pathways with the dependent on the kinds of stimuli or cell types like as chemicals. However, until present, there are a few reports to postulate molecular mechanisms of cancer therapy combined with environmental stimuli. Here, using new culture system, compressed air into two atmospheres (hydrostatic pressure, HP), we explore the molecular mechanism of HP stimulation coupled with TRAIL‐mediated apoptosis in lung carcinoma cell H460 (one of non small cell lung carcinoma cells). Interestingly, HP treatment combined with TRAIL significantly induced the apoptosis by 2.0‐fold in H460 cells compared to TRAIL only treated cells. We show the HP‐potentiating apoptosis of H460 is characterized by activation of intrinsic pathway which defined as caspase 8‐mediated Bid cleavage and subsequent the disruption of mitochondrial membrane potential and cytochrome c releases. This was accompanied by the increased ROS generation and down‐regulated inhibitor of apoptosis (IAPs) such as XIAP and survivin. HP‐enhanced apoptosis is completely abrogated by Z‐IETD‐FMK, caspase8 inhibitor. Furthermore about 37% increased expression of DR5 was observed in cells treated with TRAIL and HP. Although the HP‐induced sensitization of apoptosis also shows in another lung cancer cells and cells from different organs, human normal cells remains resistant without any damages from the treatment coupled with HP. Taken together, these findings suggest that HP as one of the mechanical and physiological stimuli, can act as an adjuvant tool for attractive cancer treatment mediated by TRAIL. Our ongoing studies are evaluating the specific mechanism of anticancer activity via TRAIL and HP using transcriptome and proteome tools and controlling initiation of apoptosis signaling in TRAIL‐based cancer therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A77.