An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma

Abstract

	•AMPK activation induces PGC-1α expression in glioblastoma during nutrient scarcity.
	•PGC-1α enables metabolic plasticity by facilitating metabolism of alternative nutrients in glioblastoma.
	•PGC-1α expression is inversely correlated with hypoxic tumour regions in human glioblastomas.

Keywords

AMP-activated protein kinase / glioblastoma / hypoxia / metabolic plasticity / PGC-1α / PPARGC1A / tumour microenvironment

References

[1] Ostrom QT, Cioffi G, Gittleman H, et al. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2012-2016. Neuro-oncology. 2019;21(5):v1-v100.

[2] Evans SM, Judy KD, Dunphy I, et al. Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res. 2004;10(24):8177-8184.

[3] Warburg O, Posener K, Negelein E. Über den Stoffwechsel der Carcinomzelle. Biochem Z. 1924(152):319-344.

[4] Frezza C, Zheng L, Tennant DA, et al. Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PLoS ONE. 2011;6(9):e24411.

[5] Lin H, Patel S, Affleck VS, et al. Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells. Neuro-oncology. 2017;19(1):43-54.

[6] Taïb B, Aboussalah AM, Moniruzzaman M, et al. Lipid accumulation and oxidation in glioblastoma multiforme. Sci Rep. 2019;9(1):19593.

[7] Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251-262.

[8] Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9(8):563-575.

[9] Chaube B, Malvi P, Singh SV, Mohammad N, Viollet B, Bhat MK. AMPK maintains energy homeostasis and survival in cancer cells via regulating p38/PGC-1α-mediated mitochondrial biogenesis. Cell Death Discov. 2015;1:15063.

[10] Rabinovitch RC, Samborska B, Faubert B, et al. AMPK maintains cellular metabolic homeostasis through regulation of mitochondrial reactive oxygen species. Cell Rep. 2017;21(1):1-9.

[11] Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α a nodal regulator of mitochondrial　biogenesis. Am J Clin Nutr. 2011;93(4):884S-890.

[12] Bruns I, Sauer B, Burger MC, et al. Disruption of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α reverts key features of the neoplastic phenotype of glioma cells. J Biol Chem. 2019;294(9):3037-3050.

[13] LeBleu VS, O’Connell JT, Gonzalez Herrera KN, et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol. 2014;16(10):992-1003.

[14] Garofano L, Migliozzi S, Oh YT, et al. Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities. Nat Cancer. 2021;2(2):141-156.

[15] Ravi VM, Will P, Kueckelhaus J, et al. Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma. Cancer Cell. 2022;40(6):639-655.

[16] Lorenz NI, Sauer B, Zeiner PS, et al. AMP-kinase mediates adaptation of glioblastoma cells to conditions of the tumour microenvironment. biorxiv. 2022.

[17] Miller SW, Trimmer PA, Parker WD, Davis RE. Creation and characterization of mitochondrial DNA-depleted cell lines with “neuronal-like” properties. J Neurochem. 1996;67(5):1897-1907.

[18] Steinbach JP, Wolburg H, Klumpp A, Probst H, Weller M. Hypoxia-induced cell death in human malignant glioma cells: energy deprivation promotes decoupling of mitochondrial cytochrome c release from caspase processing and necrotic cell death. Cell Death Differ. 2003;10(7):823-832.

[19] Wanka C, Brucker DP, Bähr O, et al. Synthesis of cytochrome C oxidase 2: a p53-dependent metabolic regulator that promotes respiratory function and protects glioma and colon cancer cells from hypoxia-induced cell death. Oncogene. 2012;31(33):3764-3776.

[20] Vandesompele J, Preter Kde, Pattyn F, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3(7).

[21] Thiepold A-L, Lorenz NI, Foltyn M, et al. Mammalian target of rapamycin complex 1 activation sensitizes human glioma cells to hypoxia-induced cell death. Brain. 2017;140(10):2623-2638.

[22] Grady JE, Lummis WL, Smith CG. An improved tissue culture assay. III. Alternate methods for measuring cell growth. Cancer Res. 1960;20:1114-1117.

[23] Roth W, Fontana A, Trepel M, Reed JC, Dichgans J, Weller M. Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics. Cancer Immunol Immunother. 1997;44(1):55-63.

[24] Ronellenfitsch MW, Brucker DP, Burger MC, et al. Antagonism of the mammalian target of rapamycin selectively mediates metabolic effects of epidermal growth factor receptor inhibition and protects human malignant glioma cells from hypoxia-induced cell death. Brain. 2009;132(6):1509-1522.

[25] Heinzen D, Divé I, Lorenz NI, Luger A-L, Steinbach JP, Ronellenfitsch MW. Second generation mTOR inhibitors as a double-edged sword in malignant glioma treatment. Int J Mol Sci. 2019;20(18).

[26] Gerstmeier J, Possmayer A-L, Bozkurt S, et al. Calcitriol promotes differentiation of glioma stem-like cells and increases their susceptibility to temozolomide. Cancers (Basel). 2021;13(14):34298790.

[27] Luthardt T, Diehl V. Galaktoseverwertung in Gewebekulturzellen [Galactose utilization in tissue culture cells]. Klin Wochenschr. 1966;44(13):774-780.

[28] Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y. Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicol Sci. 2007;97(2):539-547.

[29] Robinson BH, Petrova-Benedict R, Buncic JR, Wallace DC. Nonviability of cells with oxidative defects in galactose medium: a screening test for affected patient fibroblasts. Biochemical medicine and metabolic biology. 1992;48(2):122-126.

[30] Warburg O, Geissler AW, Lorenz S. Über Wachstum von Krebszellen in Medien, deren Glucose durch Galaktose ersetzt ist. Hoppe-Seyler’s Zeitschrift für physiologische Chemie. Biol Chem. 1967;348(Jahresband):1686-1687.

[31] Holden HM, Rayment I, Thoden JB. Structure and function of enzymes of the Leloir pathway for galactose metabolism. J Biol Chem. 2003;278(45):43885-43888.

[32] Mot AI, Liddell JR, White AR, Crouch PJ. Circumventing the Crabtree effect: a method to induce lactate consumption and increase oxidative phosphorylation in cell culture. Int J Biochem Cell Biol. 2016;79:128-138.

[33] Eriksson JA, Wanka C, Burger MC, et al. Suppression of oxidative phosphorylation confers resistance against bevacizumab in experimental glioma. J Neurochem. 2018;144(4):421-430.

[34] Yao C-H, Liu G-Y, Wang R, Moon SH, Gross RW, Patti GJ. Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of β-oxidation. PLoS Biol. 2018;16(3):e2003782.

[35] Lemos C, Schulze VK, Bader B, et al. Abstract 5873: BAY-3827, a selective inhibitor of AMPK for the evaluation of the role of AMPK in Myc-dependent tumors. Cancer Res. 2018;78:5873.

[36] Ruiz-Moreno C, Salas SM, Samuelsson E, Brandner S, Kranendonk ME, Nilsson M. Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma. bioRxiv. 2022.

[37] Neftel C, Laffy J, Filbin MG, et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell. 2019;178(4):835-849.

[38] Xiong Z, Liu H, He C, Li X. Hypoxia contributes to poor prognosis in primary IDH-wt GBM by inducing tumor cells MES-like transformation trend and inhibiting immune cells activity. Front Oncol. 2021:11782043.

[39] Maher EA, Marin-Valencia I, Bachoo RM, et al. Metabolism of U-13 Cglucose in human brain tumors in vivo. NMR Biomed. 2012;25(11):1234-1244.

[40] Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029-1033.

[41] Campbell PN. Principles of biochemistry second edition. Biochem Educ. 1993;21(2):114.

[42] Guppy M, Leedman P, Zu X, Russell V. Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J. 2002;364(1):309-315.

[43] Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA. Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res. 2004;64(3):985-993.

[44] Kodama M, Oshikawa K, Shimizu H, et al. A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer. Nat Commun. 2020;11(1):1320.

[45] Kleiner S, Mepani RJ, Laznik D, et al. Development of insulin resistance in mice lacking PGC-1α in adipose tissues. Proc Natl Acad Sci U S A. 2012;109(24):9635-9640.

[46] Yoon JC, Puigserver P, Chen G, et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001;413(6852):131-138.

[47] Besse-Patin A, Jeromson S, Levesque-Damphousse P, Secco B, Laplante M, Estall JL. PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin. Proc Natl Acad Sci U S A. 2019;116(10):4285-4290.

[48] Svensson K, Albert V, Cardel B, Salatino S, Handschin C. Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice. FASEB J. 2016;30(5):1976-1986.

[49] Miller KN, Clark JP, Martin SA, et al. PGC-1a integrates a metabolism and growth network linked to caloric restriction. Aging Cell. 2019;18(5):e12999.

[50] Nieman KM, Kenny HA, Penicka CV, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17(11):1498-1503.

[51] Feron O. Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother Oncol. 2009;92(3):329-333.

[52] Penfold L, Woods A, Pollard AE, et al. AMPK activation protects against prostate cancer by inducing a catabolic cellular state. Cell Rep. 2023;42(4):112396.

[53] Jäger S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A. 2007;104(29):12017-12022.

[54] Liu R, Zhang H, Zhang Y, et al. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor suppressor in hepatocellular carcinoma. Tumour Biol. 2017;39(4):1010428317695031.

[55] Jiang WG, Douglas-Jones A, Mansel RE. Expression of peroxisome-proliferator activated receptor-gamma (PPARgamma) and the PPARgamma co-activator, PGC-1, in human breast cancer correlates with clinical outcomes. Int J Cancer. 2003;106(5):752-757.

[56] Raggi C, Taddei ML, Sacco E, et al. Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma. J Hepatol. 2021;74(6):1373-1385.

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2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.