Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines.
Apoptosis
/ genetics
Autophagy
/ genetics
Cell Line, Tumor
Cell Proliferation
/ genetics
Coatomer Protein
/ genetics
Female
Ferritins
/ genetics
Ferroptosis
/ genetics
Glioblastoma
/ genetics
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Nuclear Receptor Coactivators
/ genetics
Oxidoreductases
/ genetics
RNA, Small Interfering
/ genetics
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
16
06
2020
accepted:
11
12
2020
revised:
25
11
2020
pubmed:
10
1
2021
medline:
31
7
2021
entrez:
9
1
2021
Statut:
ppublish
Résumé
Dysregulated iron metabolism is a hallmark of many cancers, including glioblastoma (GBM). However, its role in tumor progression remains unclear. Herein, we identified coatomer protein complex subunit zeta 1 (COPZ1) as a therapeutic target candidate which significantly dysregulated iron metabolism in GBM cells. Overexpression of COPZ1 was associated with increasing tumor grade and poor prognosis in glioma patients based on analysis of expression data from the publicly available database The Cancer Genome Atlas (P < 0.001). Protein levels of COPZ1 were significantly increased in GBM compared to non-neoplastic brain tissue samples in immunohistochemistry and western blot analysis. SiRNA knockdown of COPZ1 suppressed proliferation of U87MG, U251 and P3#GBM in vitro. Stable expression of a COPZ1 shRNA construct in U87MG inhibited tumor growth in vivo by ~60% relative to controls at day 21 after implantation (P < 0.001). Kaplan-Meier analysis of the survival data demonstrated that the overall survival of tumor bearing animals increased from 20.8 days (control) to 27.8 days (knockdown, P < 0.05). COPZ1 knockdown also led to the increase in nuclear receptor coactivator 4 (NCOA4), resulting in the degradation of ferritin, and a subsequent increase in the intracellular levels of ferrous iron and ultimately ferroptosis. These data demonstrate that COPZ1 is a critical mediator in iron metabolism. The COPZ1/NCOA4/FTH1 axis is therefore a novel therapeutic target for the treatment of human GBM.
Identifiants
pubmed: 33420375
doi: 10.1038/s41388-020-01622-3
pii: 10.1038/s41388-020-01622-3
pmc: PMC7906905
doi:
Substances chimiques
COPZ1 protein, human
0
Coatomer Protein
0
NCOA4 protein, human
0
Nuclear Receptor Coactivators
0
RNA, Small Interfering
0
Ferritins
9007-73-2
FTH1 protein, human
EC 1.-
Oxidoreductases
EC 1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1425-1439Références
Han M, Wang S, Yang N, Wang X, Zhao W, Saed HS, et al. Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma. EMBO Mol Med. 2020;12:e10924.
pubmed: 31777202
doi: 10.15252/emmm.201910924
Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro-Oncol. 2012;14 Suppl 5:v1–49.
pubmed: 23095881
pmcid: 3480240
doi: 10.1093/neuonc/nos218
Simon T, Jackson E, Giamas G. Breaking through the glioblastoma micro-environment via extracellular vesicles. Oncogene. 2020;39:4477–90.
pubmed: 32366909
pmcid: 7269906
doi: 10.1038/s41388-020-1308-2
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.
pubmed: 15758009
doi: 10.1056/NEJMoa043330
Legendre C, Garcion E. Iron metabolism: a double-edged sword in the resistance of glioblastoma to therapies. Trends Endocrinol Metab: TEM. 2015;26:322–31.
pubmed: 25936466
doi: 10.1016/j.tem.2015.03.008
Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013;13:342–55.
pubmed: 23594855
pmcid: 4036554
doi: 10.1038/nrc3495
Wang Y, Yu L, Ding J, Chen Y. Iron metabolism in cancer. Int J Mol Sci. 2018;20:1–22.
doi: 10.3390/ijms20010095
van Swelm RPL, Wetzels JFM, Swinkels DW. The multifaceted role of iron in renal health and disease. Nat Rev Nephrol. 2020;16:77–98.
pubmed: 31554933
doi: 10.1038/s41581-019-0197-5
Chen JJ, Galluzzi L. Fighting resilient cancers with iron. Trends Cell Biol. 2018;28:77–78.
pubmed: 29223642
doi: 10.1016/j.tcb.2017.11.007
Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, et al. Role of mitochondria in ferroptosis. Mol Cell. 2019;73:354–63.
pubmed: 30581146
doi: 10.1016/j.molcel.2018.10.042
Zhang Y, Fu X, Jia J, Wikerholmen T, Xi K, Kong Y, et al. Glioblastoma therapy using codelivery of cisplatin and glutathione peroxidase targeting siRNA from iron oxide nanoparticles. ACS Appl Mater interfaces. 2020;39:43408–21.
doi: 10.1021/acsami.0c12042
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.
pubmed: 28985560
pmcid: 5685180
doi: 10.1016/j.cell.2017.09.021
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.
pubmed: 22632970
pmcid: 3367386
doi: 10.1016/j.cell.2012.03.042
Salvador GA. Iron in neuronal function and dysfunction. BioFactors (Oxf, Engl). 2010;36:103–10.
doi: 10.1002/biof.80
Madsen E, Gitlin JD. Copper and iron disorders of the brain. Annu Rev Neurosci. 2007;30:317–37.
pubmed: 17367269
doi: 10.1146/annurev.neuro.30.051606.094232
Pignatello JJ, Oliveros E, MacKay A. Advanced oxidation processes for organic contaminant destruction based on the Fenton reaction and related chemistry. Crit Rev Environ Sci Technol. 2006;36:1–84.
doi: 10.1080/10643380500326564
Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26:1021–32.
pubmed: 27514700
pmcid: 5034113
doi: 10.1038/cr.2016.95
Hassannia B, Vandenabeele P, Vanden Berghe T. Targeting ferroptosis to iron out cancer. Cancer cell. 2019;35:830–49.
pubmed: 31105042
doi: 10.1016/j.ccell.2019.04.002
Murphy MP. Metabolic control of ferroptosis in cancer. Nat Cell Biol. 2018;20:1104–5.
pubmed: 30224762
doi: 10.1038/s41556-018-0209-x
Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer. 2019;19:405–14.
pubmed: 31101865
doi: 10.1038/s41568-019-0149-1
Ryu MS, Zhang D, Protchenko O, Shakoury-Elizeh M, Philpott CC. PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis. J Clin Investig. 2017;127:1786–97.
pubmed: 28375153
pmcid: 5409075
doi: 10.1172/JCI90519
Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature. 2014;509:105–9.
pubmed: 24695223
pmcid: 4180099
doi: 10.1038/nature13148
Cooper MS, Stark Z, Lunke S, Zhao T, Amor DJ. IREB2-associated neurodegeneration. Brain: a J Neurol. 2019;142:e40.
doi: 10.1093/brain/awz183
Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene. 2015;34:5617–25.
pubmed: 25728673
pmcid: 4640181
doi: 10.1038/onc.2015.32
Beck R, Ravet M, Wieland FT, Cassel D. The COPI system: Molecular mechanisms and function. FEBS Lett. 2009;583:2701–9.
pubmed: 19631211
doi: 10.1016/j.febslet.2009.07.032
Razi M, Chan EY, Tooze SA. Early endosomes and endosomal coatomer are required for autophagy. J cell Biol. 2009;185:305–21.
pubmed: 19364919
pmcid: 2700373
doi: 10.1083/jcb.200810098
Collinet C, Stoter M, Bradshaw CR, Samusik N, Rink JC, Kenski D, et al. Systems survey of endocytosis by multiparametric image analysis. Nature. 2010;464:243–9.
pubmed: 20190736
doi: 10.1038/nature08779
Mleczko-Sanecka K, Roche F, da Silva AR, Call D, D’Alessio F, Ragab A, et al. Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling. Blood. 2014;123:1574–85.
pubmed: 24385536
pmcid: 3945866
doi: 10.1182/blood-2013-07-515957
Anania MC, Cetti E, Lecis D, Todoerti K, Gulino A, Mauro G, et al. Targeting COPZ1 non-oncogene addiction counteracts the viability of thyroid tumor cells. Cancer Lett. 2017;410:201–11.
pubmed: 28951131
doi: 10.1016/j.canlet.2017.09.024
Mleczko-Sanecka K, da Silva AR, Call D, Neves J, Schmeer N, Damm G, et al. Imatinib and spironolactone suppress hepcidin expression. Haematologica. 2017;102:1173–84.
pubmed: 28385785
pmcid: 5566021
doi: 10.3324/haematol.2016.162917
Zhang Z, Yao Z, Wang L, Ding H, Shao J, Chen A, et al. Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells. Autophagy. 2018;14:2083–103.
pubmed: 30081711
pmcid: 6984765
doi: 10.1080/15548627.2018.1503146
Fruehauf JP, Meyskens FL Jr. Reactive oxygen species: a breath of life or death? Clinical cancer research: an official journal of the American Association for. Cancer Res. 2007;13:789–94.
Sosa V, Moline T, Somoza R, Paciucci R, Kondoh H, ME LL. Oxidative stress and cancer: an overview. Ageing Res Rev. 2013;12:376–90.
pubmed: 23123177
doi: 10.1016/j.arr.2012.10.004
Shin D, Lee J, You JH, Kim D, Roh JL. Dihydrolipoamide dehydrogenase regulates cystine deprivation-induced ferroptosis in head and neck cancer. Redox Biol. 2020;30:101418.
pubmed: 31931284
pmcid: 6957841
doi: 10.1016/j.redox.2019.101418
Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Sci (N. Y, NY). 2000;290:1717–21.
doi: 10.1126/science.290.5497.1717
Liu Y, Levine B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ. 2015;22:367–76.
pubmed: 25257169
doi: 10.1038/cdd.2014.143
Shtutman M, Baig M, Levina E, Hurteau G, Lim CU, Broude E, et al. Tumor-specific silencing of COPZ2 gene encoding coatomer protein complex subunit zeta 2 renders tumor cells dependent on its paralogous gene COPZ1. Proc Natl Acad Sci USA. 2011;108:12449–54.
pubmed: 21746916
pmcid: 3145676
doi: 10.1073/pnas.1103842108
Theil EC. Iron, ferritin, and nutrition. Annu Rev Nutr. 2004;24:327–43.
pubmed: 15189124
doi: 10.1146/annurev.nutr.24.012003.132212
Dowdle WE, Nyfeler B, Nagel J, Elling RA, Liu S, Triantafellow E, et al. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat Cell Biol. 2014;16:1069–79.
pubmed: 25327288
doi: 10.1038/ncb3053
Mancias JD, Pontano Vaites L, Nissim S, Biancur DE, Kim AJ, Wang X, et al. Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. eLife. 2015;4:1–19.
doi: 10.7554/eLife.10308
Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016;12:1425–8.
pubmed: 27245739
pmcid: 4968231
doi: 10.1080/15548627.2016.1187366
Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23:369–79.
pubmed: 26794443
pmcid: 5072448
doi: 10.1038/cdd.2015.158
Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013;13:342–55.
pubmed: 23594855
pmcid: 4036554
doi: 10.1038/nrc3495
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
pubmed: 21376230
doi: 10.1016/j.cell.2011.02.013
Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer. 2007;7:961–7.
pubmed: 17972889
pmcid: 2866167
doi: 10.1038/nrc2254
Janku F, McConkey DJ, Hong DS, Kurzrock R. Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol. 2011;8:528.
pubmed: 21587219
doi: 10.1038/nrclinonc.2011.71
Sukseree S, Schwarze UY, Gruber R, Gruber F, Quiles Del Rey M, Mancias JD, et al. ATG7 is essential for secretion of iron from ameloblasts and normal growth of murine incisors during aging. Autophagy. 2020;16:1851–7.
pubmed: 31880208
pmcid: 8386597
doi: 10.1080/15548627.2019.1709764
Teng J, Hejazi S, Hiddingh L, Carvalho L, de Gooijer MC, Wakimoto H, et al. Recycling drug screen repurposes hydroxyurea as a sensitizer of glioblastomas to temozolomide targeting de novo DNA synthesis, irrespective of molecular subtype. Neuro-Oncol. 2018;20:642–54.
pubmed: 29099956
doi: 10.1093/neuonc/nox198
Schoenfeld JD, Sibenaller ZA, Mapuskar KA, Wagner BA, Cramer-Morales KL, Furqan M, et al. O(2)(⋅-) and H(2)O(2)-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate. Cancer cell. 2017;31:487–500.
pubmed: 28366679
pmcid: 5497844
doi: 10.1016/j.ccell.2017.02.018