Hypoxia-mediated apoptosis in oral carcinoma cells occurs via two independent pathways

BACKGROUND: We are attempting to elucidate the mechanism of apoptotic cell death induced by hypoxia in oral cancer cells. Since hypoxia can render solid tumors more resistant to radiation and chemotherapy, understanding the pathways involved in hypoxia-induced apoptosis of oral cancer cells would be of significant therapeutic value. RESULTS: Here we showed that oral cancer cells from primary tumor and lymph node metastasis undergo apoptosis after 24 to 48 h of hypoxia. During hypoxic growth, an increase in caspase-3 proteolytic activity was observed, accompanied by the cleavage of PARP (poly (ADP-ribose) polymerase) indicative of caspase activity. In addition, hypoxic stress also lead to activation of caspase-8, -9, and -10 but not -1, elicited the release of cytochrome C into the cytosol, and resulted in internucleosomal DNA fragmentation. CONCLUSION: These results show that hypoxia-induced apoptosis in oral carcinoma cell lines relies on both intrinsic (mitochondrial) and extrinsic (cell death receptor mediated) pathways. This novel evidence will assist in designing more efficient combination chemotherapy approaches as promising strategy for the treatment of oral cancers.