| The tumor microenvironment is one of harsh nutrient stress; the interior of a tumor has restricted availability to crucial nutrients such as glucose, amino acids, growth factors, and oxygen. To adapt to the metabolic stress of the tumor microenvironment, cancer cells induce autophagy to conserve energy, recycle macromolecules, and remove damaged organelles such as mitochondria. Through the induction of autophagy and evasion of apoptosis a tumor cell is able to survive metabolic stress at the interior of a tumor, albeit in a growth arrested state.;However, tumor cells frequently lose the ability to undergo autophagy, resulting in energetic catastrophe and induction of necrosis. Necrotic cell death promotes tumor progression by eliciting an inflammatory response, which promotes proliferation, angiogenesis, and metastasis of tumor cells. An interesting dichotomy therefore, exists between the promotion of cancer cell survival through autophagy, and tumor progression induced by necrosis that is a result of dysfunctional autophagy. Understanding the response of individual cells to nutrient deprivation in terms of the type of cell death induced, is therefore critical to understanding how tumors progress.;One gene that has been reported to regulate both autophagy and cell death in response to oxygen deprivation is BNIP3. BNIP3 over-expression has been associated with cell death in hypoxic regions of tumors and ischemic heart disease, making BNIP3 an attractive candidate regulator of cell death in the hypoxic response. Recent evidence however suggests that, rather than inducing cell death, the normal function of BNIP3 is to promote survival by initiating autophagy in response to hypoxia.;This body of work set out to identify mechanisms underlying BNIP3 function in autophagy (survival) and necrosis (death). I have identified a novel mechanism to explain how BNIP3 promotes mitochondrial degradation through autophagy. BNIP3 has dual functions in mitophagy, it induces mitochondrial fragmentation, followed by targeting to the autophagosome through its interaction with LC3. In a model of necrotic cell death associated with BNIP3 expression, I showed that proteolytic cleavage of BNIP3 is mediated by caspase-1 at aspartic acid 83. This cleavage of BNIP3 disrupted the interaction of BNIP3 with LC3, and resulted in the accumulation of fragmented mitochondria. I conclude that disruption of BNIP3 function in mitophagy by caspase-1 proteolysis represents a novel mechanism by which a cell undergoes necrotic cell death, and identifies BNIP3 as the first intra-cellularly acting target of caspase-1 in cell death. |
