Mitochondrial NIX Promotes Tumor Survival in the Hypoxic Niche of Glioblastoma.

Cancer cells rely on mitochondrial functions to regulate key survival and death signals. How cancer cells regulate mitochondrial autophagy (mitophagy) in the tumor microenvironment as well as utilize mitophagy as a survival signal is still not well understood. Here we elucidate a key survival mechanism of mitochondrial NIX-mediated mitophagy within the hypoxic region of glioblastoma, the most malignant brain tumor. NIX was overexpressed in the pseudopalisading cells that envelop the hypoxic-necrotic regions, and mitochondrial NIX expression was robust in patient-derived glioblastoma tumor tissues and glioblastoma stem cells (GSC). NIX was required for hypoxia and oxidative stress-induced mitophagy through NFE2L2/NRF2 transactivation. Silencing NIX impaired mitochondrial reactive oxygen species (ROS) clearance, cancer stem cell maintenance, and HIF/mTOR/RHEB signaling pathways under hypoxia, resulting in suppression of glioblastoma survival in vitro and in vivo. Clinical significance of these findings was validated by the compelling association between NIX expression and poor outcome for glioblastoma patients. Taken together, our findings indicate that the NIX-mediated mitophagic pathway may represent a key therapeutic target for solid tumors including glioblastoma.

[1]  M. Haigis,et al.  Mitochondria and Cancer , 2016, Cell.

[2]  D. Sabatini,et al.  SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance , 2015 .

[3]  Dede N. Ekoue,et al.  MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signaling in cancer , 2014, Nature Communications.

[4]  Y. Ci,et al.  ROS inhibit autophagy by downregulating ULK1 mediated by the phosphorylation of p53 in selenite-treated NB4 cells , 2014, Cell Death and Disease.

[5]  T. Schwarz,et al.  Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin , 2014, The Journal of cell biology.

[6]  Keisuke Ito,et al.  Metabolic requirements for the maintenance of self-renewing stem cells , 2014, Nature Reviews Molecular Cell Biology.

[7]  A. García-Sastre,et al.  mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection. , 2014, Virology.

[8]  G. Stragliotto,et al.  Survival in patients with glioblastoma receiving valganciclovir. , 2013, The New England journal of medicine.

[9]  G. Semenza,et al.  HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. , 2013, The Journal of clinical investigation.

[10]  B. Bao,et al.  Overview of Cancer Stem Cells (CSCs) and Mechanisms of Their Regulation: Implications for Cancer Therapy , 2013, Current protocols in pharmacology.

[11]  M. Priault,et al.  Rheb regulates mitophagy induced by mitochondrial energetic status. , 2013, Cell metabolism.

[12]  Ray Marcel Marin-Florez,et al.  A KRAB/KAP1-miRNA Cascade Regulates Erythropoiesis Through Stage-Specific Control of Mitophagy , 2013, Science.

[13]  A. McEvoy,et al.  The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells , 2013, Oncogene.

[14]  D. Rubinsztein,et al.  Autophagy modulation as a potential therapeutic target for diverse diseases , 2012, Nature Reviews Drug Discovery.

[15]  Qiulian Wu,et al.  Platelet-derived growth factor receptors differentially inform intertumoral and intratumoral heterogeneity. , 2012, Genes & development.

[16]  J. Gronych,et al.  Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. , 2012, Cancer research.

[17]  E. Schon,et al.  Mitochondria: The Next (Neurode)Generation , 2011, Neuron.

[18]  P. Schumacker,et al.  Hypoxia Triggers AMPK Activation through Reactive Oxygen Species-Mediated Activation of Calcium Release-Activated Calcium Channels , 2011, Molecular and Cellular Biology.

[19]  Yang Liu,et al.  Targeting HIF1α eliminates cancer stem cells in hematological malignancies. , 2011, Cell stem cell.

[20]  A. Pyle,et al.  Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. , 2011, Cell stem cell.

[21]  G. Dorn,et al.  Nix Is Critical to Two Distinct Phases of Mitophagy, Reactive Oxygen Species-mediated Autophagy Induction and Parkin-Ubiquitin-p62-mediated Mitochondrial Priming* , 2010, The Journal of Biological Chemistry.

[22]  J. Pouysségur,et al.  Hypoxia-induced autophagy: cell death or cell survival? , 2010, Current opinion in cell biology.

[23]  M. Wolter,et al.  A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. , 2010, Brain : a journal of neurology.

[24]  R. Youle,et al.  Mechanisms of mitophagy , 2010, Nature Reviews Molecular Cell Biology.

[25]  J. Engh,et al.  Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α , 2009, Oncogene.

[26]  Hui Wang,et al.  Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. , 2009, Cancer cell.

[27]  K. Ryan,et al.  Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity. , 2009, Genes & development.

[28]  Irving L. Weissman,et al.  Association of reactive oxygen species levels and radioresistance in cancer stem cells , 2009, Nature.

[29]  J. Pouysségur,et al.  Hypoxia-Induced Autophagy Is Mediated through Hypoxia-Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains , 2009, Molecular and Cellular Biology.

[30]  H. Sandoval,et al.  Essential role for Nix in autophagic maturation of erythroid cells , 2008, Nature.

[31]  Guido Kroemer,et al.  Tumor cell metabolism: cancer's Achilles' heel. , 2008, Cancer cell.

[32]  B. Zhivotovsky,et al.  Mitochondria in cancer cells: what is so special about them? , 2008, Trends in cell biology.

[33]  M. You,et al.  Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb* , 2007, Journal of Biological Chemistry.

[34]  S. Sharkis,et al.  A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. , 2007, Blood.

[35]  A. Tee,et al.  Hypoxia-inducible Factor 1α Is Regulated by the Mammalian Target of Rapamycin (mTOR) via an mTOR Signaling Motif* , 2007, Journal of Biological Chemistry.

[36]  Brian Keith,et al.  Hypoxia-Inducible Factors, Stem Cells, and Cancer , 2007, Cell.

[37]  Mark W. Dewhirst,et al.  Glioma stem cells promote radioresistance by preferential activation of the DNA damage response , 2006, Nature.

[38]  Daniel J. Hoeppner,et al.  Notch signalling regulates stem cell numbers in vitro and in vivo , 2006, Nature.

[39]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[40]  P. Schumacker,et al.  Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. , 2005, Cell metabolism.

[41]  T. Burns,et al.  Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth. , 2004, Cancer cell.

[42]  E. Hafen,et al.  Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. , 2004, Genes & development.

[43]  Daniel J Brat,et al.  Pseudopalisades in Glioblastoma Are Hypoxic, Express Extracellular Matrix Proteases, and Are Formed by an Actively Migrating Cell Population , 2004, Cancer Research.

[44]  G. Dorn,et al.  Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy , 2002, Nature Medicine.