Tumor hypoxia has been shown in several clinical studies to be an independent prognostic indicator of poor patient outcome. One hypothesis connecting hypoxia and poor outcome is that tumor hypoxia can select for cancer cells that possess diminished apoptotic programs. This selection for cells that are refractory to hypoxia induced apoptosis can also select for cells that are resistant to chemotherapy, and those with increased metastatic potential. Previous studies have shown that the p53 tumor suppressor gene plays an important role in the sensitivity of oncogenically transformed cells to killing under hypoxia. However, recent data suggests that hypoxia-induced apoptosis can occur to a lesser degree in a p53-independent manner as well. Expression profiling of human squamous tumor cells exposed to hypoxia identified a class of BH3 containing pro-apoptotic genes to be coordinately induced. BNIP3 and BNIP3L are robustly elevated by hypoxia in normal and transformed cells, and have also been shown by other investigators to apoptotic stimuli. We therefore proposed to investigate the contribution of BNIP3L to hypoxia-induced apoptosis in tumor cells. We will do this in three ways: 1) block induction of BNIP3L in response to hypoxia and determine changes in hypoxia-induced apoptosis, 2) examine mitochondrial function during hypoxia as a potential mediator of BIP3L toxicity, and 3) use the yeast S. cerevisiae homozygote deletion pool to identify molecular partners of BNIP3L that can modify NIP-induced toxicity. These experiments should yield insight into how hypoxia impacts mitochondrial function both in normal and transformed cells, and how mitochondrial dysfunction is transmitted to death effectors. These findings should also lead to a better understanding of hypoxia induced death in tumor cells, and how novel therapies could be designed specifically to take advantage of these pathways.
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