One-carbon-mediated purine synthesis underlies temozolomide resistance in glioblastoma.
Temozolomide
/ pharmacology
Glioblastoma
/ metabolism
Humans
Drug Resistance, Neoplasm
/ drug effects
Purines
/ pharmacology
Cell Line, Tumor
Brain Neoplasms
/ drug therapy
Cell Proliferation
/ drug effects
Carbon
/ metabolism
Animals
Aminoimidazole Carboxamide
/ analogs & derivatives
Mice
Antineoplastic Agents, Alkylating
/ therapeutic use
Ribonucleotides
/ pharmacology
Dacarbazine
/ pharmacology
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
25 Oct 2024
25 Oct 2024
Historique:
received:
29
04
2024
accepted:
18
10
2024
revised:
30
09
2024
medline:
26
10
2024
pubmed:
26
10
2024
entrez:
25
10
2024
Statut:
epublish
Résumé
Glioblastoma accounts for nearly half of all primary malignant brain tumors in adults, and despite an aggressive standard of care, including excisional surgery and adjuvant chemoradiation, recurrence remains universal, with an overall median survival of 14.6 months. Recent work has revealed the importance of passenger mutations as critical mediators of metabolic adaptation in cancer progression. In our previous work, we identified a role for the epigenetic modifier ID-1 in temozolomide resistance in glioblastoma. Here, we show that ID-1-mediated glioblastoma tumourigenesis is accompanied by upregulation of one-carbon (1-C) mediated de novo purine synthesis. ID-1 knockout results in a significant reduction in the expression of 1-C metabolism and purine synthesis enzymes. Analysis of glioblastoma surgical specimens at initial presentation and recurrence reveals that 1-C purine synthesis metabolic enzymes are enriched in recurrent glioblastoma and that their expression correlates with a shorter time to tumor recurrence. Further, we show that the 1-C metabolic phenotype underlies proliferative capacity and temozolomide resistance in glioblastoma cells. Supplementation with exogenous purines restores proliferation in ID-1-deficient cells, while inhibition of purine synthesis with AICAR sensitizes temozolomide-resistant glioblastoma cells to temozolomide chemotherapy. Our data suggest that the metabolic phenotype observed in treatment-resistant glioma cells is a potential therapeutic target in glioblastoma.
Identifiants
pubmed: 39455562
doi: 10.1038/s41419-024-07170-y
pii: 10.1038/s41419-024-07170-y
doi:
Substances chimiques
Temozolomide
YF1K15M17Y
Purines
0
Carbon
7440-44-0
Aminoimidazole Carboxamide
360-97-4
Antineoplastic Agents, Alkylating
0
AICA ribonucleotide
F0X88YW0YK
Ribonucleotides
0
purine
W60KTZ3IZY
Dacarbazine
7GR28W0FJI
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
774Informations de copyright
© 2024. The Author(s).
Références
Guo D, Hildebrandt IJ, Prins RM, Soto H, Mazzotta MM, Dang J, et al. The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. Proc Natl Acad Sci USA. 2009; 106:12932–7.
Ghannad-Zadeh K, Das S. One-carbon metabolism associated vulnerabilities in glioblastoma: a review. Cancers. 2021;13:3067.
doi: 10.3390/cancers13123067
pubmed: 34205450
pmcid: 8235277
Noguchi K, Konno M, Koseki J, Nishida N, Kawamoto K, Yamada D, et al. The mitochondrial one-carbon metabolic pathway is associated with patient survival in pancreatic cancer. Oncol Lett. 2018;16:1827–34.
pubmed: 30008872
pmcid: 6036444
Nishimura T, Nakata A, Chen X, Nishi K, Meguro-Horike M, Sasaki S, et al. Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2. Oncogene. 2019;38:2464–81.
doi: 10.1038/s41388-018-0589-1
pubmed: 30532069
Yin J, Ren W, Huang X, Deng J, Li T, Yin Y. Potential mechanisms connecting purine metabolism and cancer therapy. Front Immunol. 2018;9:1697.
Zgheib R, Battaglia-Hsu SF, Hergalant S, Quéré M, Alberto JM, Chéry C, et al. Folate can promote the methionine-dependent reprogramming of glioblastoma cells towards pluripotency. Cell Death Dis. 2019;10:1–12.
doi: 10.1038/s41419-019-1836-2
Nilsson R, Jain M, Madhusudhan N, Sheppard NG, Strittmatter L, Kampf C, et al. Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. 2014;5:3128.
doi: 10.1038/ncomms4128
pubmed: 24451681
Wang X, Yang K, Xie Q, Wu Q, Mack SC, Shi Y, et al. Purine synthesis promotes maintenance of brain tumor initiating cells in glioma. Nat Neurosci. 2017;20:661–73.
doi: 10.1038/nn.4537
pubmed: 28346452
pmcid: 6015494
Lamb R, Harrison H, Smith DL, Townsend PA, Jackson T, Ozsvari B, et al. Targeting tumor-initiating cells: eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction. Oncotarget. 2015;6:4585–601.
doi: 10.18632/oncotarget.3278
pubmed: 25671304
pmcid: 4467101
Zhang J, Nuebel E, Daley GQ, Koehler CM, Teitell MA. Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. Cell Stem Cell. 2012;11:589–95.
doi: 10.1016/j.stem.2012.10.005
pubmed: 23122286
pmcid: 3492890
Sachdeva R, Wu M, Johnson K, Kim H, Celebre A, Shahzad U, et al. BMP signaling mediates glioma stem cell quiescence and confers treatment resistance in glioblastoma. Sci Rep. 2019;9. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6787003/ .
Lasorella A, Benezra R, Iavarone A. The ID proteins: master regulators of cancer stem cells and tumour aggressiveness. Nat Rev Cancer. 2014;14: 77–91.
Nam HS, Benezra R. High levels of Id1 expression define B1 type adult neural stem cells. Cell Stem Cell. 2009;5:515–26.
doi: 10.1016/j.stem.2009.08.017
pubmed: 19896442
pmcid: 2775820
Sachdeva R, Wu M, Smiljanic S, Kaskun O, Ghannad-Zadeh K, Celebre A. et al. ID1 is critical for tumorigenesis and regulates chemoresistance in glioblastoma. Cancer Res. 2019. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31292163 .
Soroceanu L, Murase R, Limbad C, Singer E, Allison J, Adrados I, et al. Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. Cancer Res. 2013;73:1559–69.
doi: 10.1158/0008-5472.CAN-12-1943
pubmed: 23243024
Sharma BK, Kolhe R, Black SM, Keller JR, Mivechi NF, Satyanarayana A. Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells. FASEB J. 2016;30:262–75.
doi: 10.1096/fj.15-277749
pubmed: 26330493
Yin X, Tang B, Li JH, Wang Y, Zhang L, Xie XY, et al. ID1 promotes hepatocellular carcinoma proliferation and confers chemoresistance to oxaliplatin by activating pentose phosphate pathway. J Exp Clin Cancer Res. 2017;36:166.
doi: 10.1186/s13046-017-0637-7
pubmed: 29169374
pmcid: 5701377
Kuznetsov JN, Leclerc GMGJ, Leclerc GMGJ, Barredo JC. AMPK and Akt determine apoptotic cell death following perturbations of one-carbon metabolism by regulating ER stress in acute lymphoblastic leukemia. Mol Cancer Ther. 2011;10:437–47.
doi: 10.1158/1535-7163.MCT-10-0777
pubmed: 21262957
pmcid: 3053424
Zhang S, Sheng H, Zhang X, Qi Q, Chan CB, Li L, et al. Cellular energy stress induces AMPK-mediated regulation of glioblastoma cell proliferation by PIKE-A phosphorylation. Cell Death Dis. 2019;10:1–13.
Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011;13:1016–23.
doi: 10.1038/ncb2329
pubmed: 21892142
pmcid: 3249400
Asby DJ, Cuda F, Beyaert M, Houghton FD, Cagampang FR, Tavassoli A. AMPK activation via modulation of de novo purine biosynthesis with an inhibitor of ATIC homodimerization. Chem Biol. 2015. Available from: https://research-information.bris.ac.uk/en/publications/ampk-activation-via-modulation-of-de-novo-purine-biosynthesis-wit .
Sengupta TK, Leclerc GM, Hsieh-Kinser TT, Leclerc GJ, Singh I, Barredo JC. Cytotoxic effect of 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) on childhood acute lymphoblastic leukemia (ALL) cells: Implication for targeted therapy. Mol Cancer. 2007;6:46.
doi: 10.1186/1476-4598-6-46
pubmed: 17623090
pmcid: 1948012
Rae C, Mairs RJ, Rae C, Mairs RJ. AMPK activation by AICAR sensitizes prostate cancer cells to radiotherapy. Oncotarget. 2019; Available from: https://www.oncotarget.com/article/26598/text/ .
Nakamizo A, Miyamatsu Y, Hirose H, Amano T, Matsuo S, Fujiwara M, et al. Metabolic remodeling of pyrimidine synthesis pathway and serine synthesis pathway in human glioblastoma. Sci Rep. 2022;12. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9522918/ .
Locasale JW. Serine, glycine and the one-carbon cycle: cancer metabolism in full circle. Nat Rev Cancer. 2013;13:572.
doi: 10.1038/nrc3557
pubmed: 23822983
pmcid: 3806315
Barfeld SJ, Fazli L, Persson M, Marjavaara L, Urbanucci A, Kaukoniemi KM, et al. Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer. Oncotarget. 2015;6:12587–602.
doi: 10.18632/oncotarget.3494
pubmed: 25869206
pmcid: 4494960
Goswami MT, Chen G, Chakravarthi BVSK, Pathi SS, Anand SK, Carskadon SL, et al. Role and regulation of coordinately expressed de novo purine biosynthetic enzymes PPAT and PAICS in lung cancer. Oncotarget. 2015;6:23445–61.
doi: 10.18632/oncotarget.4352
pubmed: 26140362
pmcid: 4695129
Bahreyni A, Samani SS, Rahmani F, Behnam-Rassouli R, Khazaei M, Ryzhikov M, et al. Role of adenosine signaling in the pathogenesis of breast cancer. J Cell Physiol. 2018;233:1836–43.
Racanelli AC, Rothbart SB, Heyer CL, Moran RG. Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition. Cancer Res. 2009;69:5467–74.
doi: 10.1158/0008-5472.CAN-08-4979
pubmed: 19549896
pmcid: 2706929
Rattan R, Giri S, Singh AK, Singh I. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. J Biol Chem. 2005;280:39582–93.
doi: 10.1074/jbc.M507443200
pubmed: 16176927
Villa E, Ali ES, Sahu U, Ben-Sahra I. Cancer cells tune the signaling pathways to empower de novo synthesis of nucleotides. Cancers. 2019;11:688.
Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab. 2017;25:27–42.
Zhang J, F.G. Stevens M, D. Bradshaw T. Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharm. 2011;5:102–14.
doi: 10.2174/1874467211205010102
Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7:1–7.
doi: 10.1038/s41598-017-17204-5
Rabinowitz JD, Kimball E. Acidic acetonitrile for cellular metabolome extraction from Escherichia coli. Anal Chem. 2007;79:6167–73.
doi: 10.1021/ac070470c
pubmed: 17630720