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Mitochondrial NIX Promotes Tumor Survival in the Hypoxic Niche of Glioblastoma

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Mitochondrial NIX Promotes Tumor Survival in the Hypoxic Niche of Glioblastoma Published OnlineFirst September 5, 2019; DOI: 10.1158/0008-5472.CAN-19-0198 Cancer Molecular Cell Biology Research Mitochondrial NIX Promotes Tumor Survival in the Hypoxic Niche of Glioblastoma Jinkyu Jung1,Ying Zhang2, Orieta Celiku1,Wei Zhang1, Hua Song1, Brian J.Williams3, Amber J. Giles1, Jeremy N. Rich4, Roger Abounader2, Mark R. Gilbert1, and Deric M. Park1,5 Abstract Cancer cells rely on mitochondrial functions to regulate key survival and death signals. How cancer cells regulate mitochondrial autophagy (mito- phagy) 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 mito- phagy within the hypoxic region of glioblastoma, the most malignant brain tumor. NIX was over- expressed in the pseudopalisading cells that envel- op the hypoxic–necrotic regions, and mitochon- drial NIX expression was robust in patient-derived glioblastoma tumor tissues and glioblastoma stem cells. NIX was required for hypoxia and oxidative stress–induced mitophagy through NFE2L2/NRF2 transactivation. Silencing NIX impaired mitochon- drial reactive oxygen species 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 patients with glioblastoma. Taken together, our findings indicate that the NIX-mediated mitophagic pathway may represent a key therapeutic target for solid tumors, including glioblastoma. Significance: NIX-mediated mitophagy regulates tumor survival in the hypoxic niche of glioblastoma microenvironment, providing a potential therapeutic target for glioblastoma. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5218/F1.large.jpg. Introduction median survival of 12 to 14 months with a 2-year survival rate Glioblastoma is the most aggressive and common primary between 15% and 26%; this dismal survival has not significantly brain cancer. Multimodality treatment consisting of surgery, changed over the decades despite rapid advances in the clinical external beam radiotherapy, and chemotherapy merely yields a sciences and basic research efforts (1). 1Neuro-Oncology Branch, NCI, NIH, Bethesda, Maryland. 2Department of Micro- Corresponding Authors: Deric M. Park, The University of Chicago, 5841 biology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, S. Maryland Avenue, Chicago, IL 60637. Phone: 773-702-3510; Fax: 773-702- Virginia. 3Department of Neurosurgery, University of Louisville, Louisville, 9060; E-mail: [email protected]; and Jinkyu Jung, Center for Cancer Kentucky. 4Department of Medicine, Division of Regenerative Medicine, Research, National Cancer Institute, Building 37, Room 1142B, 31 Center Drive, University of California-San Diego School of Medicine, La Jolla, California. Bethesda, MD 20892. Phone: 301-760-7051; E-mail: [email protected] 5Neuro-Oncology Section, Department of Neurology, and the Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Cancer Res 2019;79:1–15 Chicago, Illinois. doi: 10.1158/0008-5472.CAN-19-0198 Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Ó2019 American Association for Cancer Research. www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst September 5, 2019; DOI: 10.1158/0008-5472.CAN-19-0198 Jung et al. Macroautophagy (hereafter autophagy) in the tumor micro- Intracranial xenograft environment is a major contributor to tumor recurrence and is All animal procedures were approved by the Animal Care and tightly coupled with increased resistance to radiotherapy and Use Committee at the University of Virginia. U251 cells (1 Â 105) chemotherapy. Autophagy process includes the degradation of that stably express either sh-Control or sh-Nix were stereotacti- dysfunctional mitochondria through mitochondrial autophagy cally injected into the striatum of SCID Balb/c mice. Three weeks (mitophagy), the cytoprotective process that controls the pro- after tumor implantation, the tumor formation was evaluated duction of reactive oxygen species (ROS) and the elimination using ClinScan animal MRI scanner and the mice survival was of damaged mitochondria (2). It is well established that hyp- further determined. oxia promotes tumor growth and resistance to therapy in cancers (3). The importance of hypoxia-inducible factors-1 a Chemicals, plasmids, and cloning and 2a (HIF1a and HIF2a) signaling for optimal function Chemicals were routinely purchased from chemical supply and survival of glioblastoma stem cells (GSC) have been companies: TBHQ and H2O2 (Sigma-Aldrich); DMOG (Tocris). previously characterized (4, 5). Indeed, we previously showed Plasmids were from the following companies: hypoxia response that hypoxia promotes preferential expansion of CD133-pos- element (HRE)-luciferase (Addgene #26731); pGL2-basic (Pro- itive GSC through a HIF1a-dependent mechanism (6). Hyp- mega); and Nix-flag (OriGene). For Nix-1195/þ114 promoter oxia and subsequent stabilization of HIF1a seem to further construct (P1), the sequence from genomic DNA of U87 cells contribute to cancer pathogenesis through induction of BNIP3 was amplified with Nix-1195F-SmaI and Nixþ114R-BglII (50- and BNIP3-like (BNIP3L or NIX) pathways resulting in AACCCGGGACAAGTCCATTTTTAAGTTC-30 and 50-TCGGAGA- enhanced tumor survival and progression (7). Subsequent TCTGGCAGGACTGC-30). Nix-1195/-151 (P2) and Nix-290/ reports link autophagy and glioblastoma tumorigenesis in GSC þ114 (P3) were amplified with Nix-1195F-SmaI and Nix- models (8, 9). However, the underlying mechanism by which 151R-BglII (50-AACCCGGGACAAGTCCATTTTTAAGTT C-30 hypoxia-induced autophagy promotes glioblastoma pathogen- and 50-AGATCTATGGGATGAGTGATGCCAGT-30); Nix-290F- esis remains unclear. NheI and Nixþ114R-BglII (50-GAGTCCTAAGAGCTAGCAAACA- Although NIX has been identified as a proapoptotic protein GATG-30 and 50-TCGGAGATCTGGCAGGACTGC-30), respective- with a BCL-2 homology 3 (BH3) domain that mediates p53- ly. These sequences (P1P3) were subcloned into pGL2-basic dependent apoptosis (10), additional functions of NIX are being vector. Nix-DARE mutants (P4P6) were derived from pGL2-Nix- discovered. For example, the truncated form of NIX, termed sNIX, 290/þ114 (P3) by substituting the potential ARE sequences. The prevents NIX-mediated apoptosis by heterodimerization with substitution was performed by Q5 site-directed mutagenesis kit NIX (11). Also, NIX-mediated mitophagy is required for mito- (New England BioLabs) according to manufacturer's instruction chondrial clearance during maturation of reticulocytes (12), using with the following primers: for P4, DARE-B-F and DARE-B-R HIF1a-induced autophagy (7), and ROS-induced autop- (50-CCGGTCATAACAAGAATCACGCAAGAGTTC-30 and 50-ATG- hagy (13). Yet, how NIX supports tumor growth in hypoxic GGATGAGTGATGCCAGTGGCAG-30); for P5, DARE-C-F and condition remains murky. Here, we investigated a key function DARE-C-R (50-GTCAGCCAATCTCGAAAGTCTCCACGTCCG-30 of NIX in the glioblastoma microenvironment and its relationship and 50-GCGCGCGCCGGGAACGAACTCTTG-30); and, for P6, with low oxygen and oxidative stress. Improved understanding of DARE-D-F and DARE-D-R (50-GTGTTAATGCCAATGTGCAA- the relationship between NIX-mediated mitophagy and HIF- GAGACGGTCCTG-30 and 50-AACAAGCCGAGTCCGCCGC- signaling cascade should contribute to elucidating the mechan- CCCCTTTT C-30). isms of glioblastoma treatment resistance. Imaging of MitoTimer and mitochondrial superoxide pMitoTimer was gifted from Dr. Zhen Yan (University of Materials and Methods Virginia). For comparison of mitochondrial fission and fusion Human glioma patient tissues, cell culture, and Mycoplasma between sh-Control and sh-Nix, cells were fixed and stained testing with DAPI. The fluorescence was excited with 488-nm laser. For Human glioblastoma, low-grade gliomas, and normal brain superoxide and mitochondria detection, cells were incubated tissues were obtained after surgery from patients at the Uni- with 2 mmol/L MitoSOX Red Mitochondrial Superoxide Indi- versity of Pittsburgh (Pittsburgh, PA) and the University of cator (Invitrogen) and 100 nmol/L MitoTracker Green FM Virginia (Charlottesville, VA). GSCs,XO-1,XO-4,XO-6,XO-8, (Invitrogen) for 10 minutes at 37C in the dark. The cells were XO-10, and 1228, were isolated from surgical specimens of gently washed three times with warm buffer and observed by patients with glioblastoma. As previously described (14), GSCs fluorescence microscopy. were maintained as tumorsphere cultures in DMEM/F12 (Gibco, #11320-033) supplemented with B27 supplement Transfection of siRNAs, shRNA lentiviral particles, and (Gibco), 20 ng/mL EGF, 20 ng/mL bFGF, and penicillin/strep- plasmids tomycin,. Normal human astrocytes (NHA) were from Lonza All cells were transfected with Lipofectamine 2000 (for plas- and cultured according to the manufacturer's protocol. mid, Invitrogen) and Lipofectamine RNAiMAX (for siRNA, Invi- Glioblastoma cell lines were purchased from ATCC and cul- trogen) according to the manufacturer's methods. siRNAs against tured in the following DMEM (Gibco, #11965-092) including the following genes were purchased from Santa Cruz Biotechnol- 10% FBS and penicillin/streptomycin.
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