Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment.
Carbohydrate Metabolism
/ genetics
Carcinoma, Hepatocellular
/ genetics
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
/ genetics
Genetic Heterogeneity
Glucose
/ metabolism
Humans
Lipid Metabolism
/ genetics
Liver Neoplasms
/ genetics
Models, Theoretical
Nitrogen
/ metabolism
Signal Transduction
/ genetics
kinetic modeling
liver
mathematical model
metabolism
tumor metabolism
Journal
The FEBS journal
ISSN: 1742-4658
Titre abrégé: FEBS J
Pays: England
ID NLM: 101229646
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
revised:
01
09
2020
received:
17
04
2020
accepted:
05
10
2020
pubmed:
9
10
2020
medline:
21
7
2021
entrez:
8
10
2020
Statut:
ppublish
Résumé
Metabolic reprogramming is a characteristic feature of cancer cells, but there is no unique metabolic program for all tumors. Genetic and gene expression studies have revealed heterogeneous inter- and intratumor patterns of metabolic enzymes and membrane transporters. The functional implications of this heterogeneity remain often elusive. Here, we applied a systems biology approach to gain a comprehensive and quantitative picture of metabolic changes in individual hepatocellular carcinoma (HCC). We used protein intensity profiles determined by mass spectrometry in samples of 10 human HCCs and the adjacent noncancerous tissue to calibrate Hepatokin1, a complex mathematical model of liver metabolism. We computed the 24-h profile of 18 metabolic functions related to carbohydrate, lipid, and nitrogen metabolism. There was a general tendency among the tumors toward downregulated glucose uptake and glucose release albeit with large intertumor variability. This finding calls into question that the Warburg effect dictates the metabolic phenotype of HCC. All tumors comprised elevated β-oxidation rates. Urea synthesis was found to be consistently downregulated but without compromising the tumor's capacity for ammonia detoxification owing to increased glutamine synthesis. The largest intertumor heterogeneity was found for the uptake and release of lactate and the size of the cellular glycogen content. In line with the observed metabolic heterogeneity, the individual HCCs differed largely in their vulnerability against pharmacological treatment with metformin. Taken together, our approach provided a comprehensive and quantitative characterization of HCC metabolism that may pave the way for a computational a priori assessment of pharmacological therapies targeting metabolic processes of HCC.
Substances chimiques
Glucose
IY9XDZ35W2
Nitrogen
N762921K75
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2332-2346Informations de copyright
© 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Références
El-Serag HB & Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132, 2557-2576.
Petta S & Craxi A (2010) Hepatocellular carcinoma and non-alcoholic fatty liver disease: from a clinical to a molecular association. Curr Pharm Des 16, 741-752.
Geschwind JF, Georgiades CS, Ko YH & Pedersen PL (2004) Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma. Expert Rev Anticancer Ther 4, 449-457.
Herling A, Konig M, Bulik S & Holzhutter HG (2011) Enzymatic features of the glucose metabolism in tumor cells. FEBS J 278, 2436-2459.
Lo CH, Farina F, Morris HP & Weinhouse S (1968) Glycolytic regulation in rat liver and hepatomas. Adv Enzyme Regul 6, 453-464.
Warburg O, Wind F & Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8, 519-530.
Warburg O (1956) On respiratory impairment in cancer cells. Science 124, 269-270.
Warburg O (1956) On the origin of cancer cells. Science 123, 309-314.
Gentric G, Mieulet V & Mechta-Grigoriou F (2017) Heterogeneity in cancer metabolism: new concepts in an old field. Antioxid Redox Signal 26, 462-485.
Lu LC, Hsu CH, Hsu C & Cheng AL (2016) Tumor heterogeneity in hepatocellular carcinoma: facing the challenges. Liver Cancer 5, 128-138.
Nabi K & Le A (2018) The intratumoral heterogeneity of cancer metabolism. Adv Exp Med Biol 1063, 131-145.
Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, Clish CB, Granter SR, Widlund HR, Spiegelman BM et al. (2013) PGC1alpha expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23, 287-301.
Strickaert A, Saiselet M, Dom G, De Deken X, Dumont JE, Feron O, Sonveaux P & Maenhaut C (2017) Cancer heterogeneity is not compatible with one unique cancer cell metabolic map. Oncogene 36, 2637-2642.
Creixell P, Reimand J, Haider S, Wu G, Shibata T, Vazquez M, Mustonen V, Gonzalez-Perez A, Pearson J, Sander C et al. (2015) Pathway and network analysis of cancer genomes. Nat Methods 12, 615-621.
Bulik S, Holzhutter HG & Berndt N (2016) The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism-insights from mathematical modeling. BMC Biol 14, 15.
Berndt N, Eckstein J, Heucke N, Gajowski R, Stockmann M, Meierhofer D & Holzhutter HG (2019) Characterization of lipid and lipid droplet metabolism in human HCC. Cells 8, 512.
Berndt N, Bulik S, Wallach I, Wunsch T, Konig M, Stockmann M, Meierhofer D & Holzhutter HG (2018) HEPATOKIN1 is a biochemistry-based model of liver metabolism for applications in medicine and pharmacology. Nat Commun 9, 2386.
Edge SB & Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17, 1471-1474.
Stockmann M, Lock JF, Malinowski M, Niehues SM, Seehofer D, Neuhaus P. The LiMAx test: a new liver function test for predicting postoperative outcome in liver surgery. HPB. 2010;12:139-146. http://dx.doi.org/10.1111/j.1477-2574.2009.00151.x.
Desmet VJ, Gerber M, Hoofnagle JH, Manns M & Scheuer PJ (1994) Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 19, 1513-1520.
Bulik S, Grimbs S, Huthmacher C, Selbig J & Holzhutter HG (2009) Kinetic hybrid models composed of mechanistic and simplified enzymatic rate laws - a promising method for speeding up the kinetic modelling of complex metabolic networks. FEBS J 276, 410-424.
Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, Glasauer A, Dufour E, Mutlu GM, Budigner GS et al. (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 3, e02242.
Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ et al. (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542-546.
Bonora M & Pinton P (2014) The mitochondrial permeability transition pore and cancer: molecular mechanisms involved in cell death. Front Oncol 4, 302.
Ly JD, Grubb DR & Lawen A (2003) The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 8, 115-128.
Beylot M, Peroni O, Diraison F & Large V (1996) New methods for in vivo studies of hepatic metabolism. Reprod Nutr Dev 36, 363-373.
Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, Kim J, Jiang L, Ko B, Skelton R, Loudat L et al. (2016) Metabolic heterogeneity in human lung tumors. Cell 164, 681-694.
Berndt N, Egners A, Mastrobuoni G, Vvedenskaya O, Fragoulis A, Dugourd A, Bulik S, Pietzke M, Bielow C, van Gassel R et al. (2019) Kinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer. Br J Cancer 122, 233-244.
Wang H, Lu J, Dolezal J, Kulkarni S, Zhang W, Chen A, Gorka J, Mandel JA & Prochownik EV (2019) Inhibition of hepatocellular carcinoma by metabolic normalization. PLoS One 14, e0218186.
Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT et al. (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762-765.
Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58-62.
Semenza GL (2008) Tumor metabolism: cancer cells give and take lactate. J Clin Invest 118, 3835-3837.
Konig M, Holzhutter HG & Berndt N (2013) Metabolic gradients as key regulators in zonation of tumor energy metabolism: a tissue-scale model-based study. Biotechnol J 8, 1058-1069.
Shang RZ, Qu SB & Wang DS (2016) Reprogramming of glucose metabolism in hepatocellular carcinoma: progress and prospects. World J Gastroenterol 22, 9933-9943.
Wang B, Hsu SH, Frankel W, Ghoshal K & Jacob ST (2012) Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha. Hepatology 56, 186-197.
He G & Karin M (2011) NF-kappaB and STAT3 - key players in liver inflammation and cancer. Cell Res 21, 159-168.
Hirata H, Sugimachi K, Komatsu H, Ueda M, Masuda T, Uchi R, Sakimura S, Nambara S, Saito T, Shinden Y et al. (2016) Decreased expression of fructose-1,6-bisphosphatase associates with glucose metabolism and tumor progression in hepatocellular carcinoma. Cancer Res 76, 3265-3276.
Favaro E, Bensaad K, Chong MG, Tennant DA, Ferguson DJ, Snell C, Steers G, Turley H, Li JL, Gunther UL et al. (2012) Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab 16, 751-764.
Lea MA, Murphy P & Morris HP (1972) Glycogen metabolism in regenerating liver and liver neoplasms. Cancer Res 32, 61-66.
Teryukova NP, Malkova VV, Sakhenberg EI, Ivanov VA, Bezborodkina NN & Snopov SA (2018) On reprogramming of tumor cells metabolism: detection of glycogen in the cell lines of hepatocellular origin with various degrees of dedifferentiation. Cytotechnology 70, 879-890.
Senni N, Savall M, Cabrerizo Granados D, Alves-Guerra MC, Sartor C, Lagoutte I, Gougelet A, Terris B, Gilgenkrantz H, Perret C et al. (2019) beta-catenin-activated hepatocellular carcinomas are addicted to fatty acids. Gut 68, 322-334.
Calvisi DF, Wang C, Ho C, Ladu S, Lee SA, Mattu S, Destefanis G, Delogu S, Zimmermann A, Ericsson J et al. (2011) Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology 140, 1071-1083.
Hao Q, Li T, Zhang X, Gao P, Qiao P, Li S & Geng Z (2014) Expression and roles of fatty acid synthase in hepatocellular carcinoma. Oncol Rep 32, 2471-2476.
Che L, Paliogiannis P, Cigliano A, Pilo MG, Chen X & Calvisi DF (2019) Pathogenetic, prognostic, and therapeutic role of fatty acid synthase in human hepatocellular carcinoma. Front Oncol 9.
Mah CY, Nassar ZD, Swinnen JV & Butler LM (2020) Lipogenic effects of androgen signaling in normal and malignant prostate. Asian J Urol 7, 258-270.
Yang Z, Qin W, Chen Y, Yuan B, Song X, Wang B, Shen F, Fu J & Wang H (2018) Cholesterol inhibits hepatocellular carcinoma invasion and metastasis by promoting CD44 localization in lipid rafts. Cancer Lett 429, 66-77.
Liu H, Dong H, Robertson K & Liu C (2011) DNA methylation suppresses expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) in human hepatocellular carcinoma. Am J Pathol 178, 652-661.
Wasfy RE & Shams Eldeen AA (2015) Roles of combined glypican-3 and glutamine synthetase in differential diagnosis of hepatocellular lesions. Asian Pac J Cancer Prev 16, 4769-4775.
Deng Y, Li X, Li X, Zheng Z, Huang W, Chen L, Tong Q & Ming Y (2018) Corilagin induces the apoptosis of hepatocellular carcinoma cells through the mitochondrial apoptotic and death receptor pathways. Oncol Rep 39, 2545-2552.
Hamilton SR & Aaltonen LA (2000) Pathology and Genetics of Tumours of the Digestive System. IARCPress, Lyon.
Cox J & Mann M (2008) MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 26, 1367-1372.
Gielisch I & Meierhofer D (2015) Metabolome and proteome profiling of complex I deficiency induced by rotenone. J Proteome Res 14, 224-235.
Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV & Mann M (2011) Andromeda: a peptide search engine integrated into the MaxQuant environment. J Proteome Res 10, 1794-1805.