The role of the hypoxia-inducible BH3-only proteins BNIP3 and BNIP3L in cancer

In this review, we summarize current knowledge of the biological functions of the atypical BH3-only proteins BNIP3 and BNIP3L, focusing on the role of these proteins in cancer. Hypoxia increases the expression of BNIP3 through the transcription factor HIF-1, but despite a considerable number of investigations, it has proven difficult to establish a clear role for BNIP3 in the cellular hypoxic response. BNIP3 can induce a form of cell death that shows features of both necrosis and apoptosis, but unusually for a BH3-only protein, death occurs independently of the BH3 domain and is critically dependent on a C-terminal transmembrane domain, which also localizes the protein to the mitochondria. BNIP3 expression does not always result in cell death, suggesting that additional factors may suppress BNIP3 or cooperate with it to induce death. BNIP3 is highly expressed in some tumors, including those of the breast, lung and cervix. However, in colorectal and pancreatic cancers BNIP3 is frequently epigenetically silenced, possibly reflecting different functions for BNIP3 in different tissues. Recent reports have shown that BNIP3 can induce autophagy and there is some evidence to suggest this may represent an emerging role for BH3-only proteins in general. However, the mechanism through which BNIP3 induces autophagy and the cellular consequences of this are yet to be established.