CBIO-28NIX PROMOTES GLIOBLASTOMA CELL SURVIVAL UNDER STRESS THROUGH MITOPHAGY

Abstract

Nix (NIP3-like protein X, BNIP3L), a hypoxia-responsive member of the Bcl-2 family of proteins, is believed to play key roles in both hypoxia-mediated cell death and mitophagy. Because our previous work demonstrated that hypoxia, a potentially stressful condition, promotes preferential expansion of GBM stem-like cells in a HIF-1-dependent mechanism, we investigated Nix in GBM. We observed elevated levels of mitochondrial Nix and LC3B-II/I ratio in GBM tissues. Series of experiments revealed that Nix but not BNIP3, mediated hypoxia-induced mitophagy in an Nrf2 (critical regulator of the cellular antioxidant response)-dependent manner. Nix repression led to several striking observations: 1) Reversal of hypoxia-mediated GBM cell proliferation; 2) Down-regulation of both HIF-1α and HIF-2α; 3) Inhibition of Rheb and its downstream signaling; 4) Depletion of cellular ATP level; and 5) Decreased survival of animals in orthotopic xenograft GBM model. Both oncogenic and tumor suppressive actions of autophagy have been extensively discussed in the literature, supporting the notion that specific action is likely cell-type and context dependent. Our work suggests that Nix regulation of mitophagy is a critical mechanism of GBM cell survival particularly during stressful conditions. Such conclusion is further support by pronounced sensitivity of Nix depleted GBM cells to temozolomide and/or irradiation. Manipulation of the Nix pathway may provide novel therapeutic opportunities.