Abrogation of De novo Lipogenesis by Stearoyl-CoA Desaturase 1 Inhibition Interferes with Oncogenic Signaling and Blocks Prostate Cancer Progression in Mice

Molecular Cancer Therapeutics - Tập 9 Số 6 - Trang 1740-1754 - 2010
Vanessa Fritz1, Zohra Benfodda1, Geneviève Rodier1, Corinne Henriquet1, François Iborra1, Christophe Avancès1, Yves Allory1, Alexandre de la Taille1, Stéphane Culine1, H. Blancou1, Jean‐Paul Cristol1, Françoise Michel1, Claude Sardet1, Lluís Fajas1
1Authors' Affiliations: 1Institut de Recherche en Cancérologie de Montpellier; 2INSERM, U896; 3Université de Montpellier 1; 4CRLC Val d'Aurelle Paul Lamarque; 5Institut de Génétique Moléculaire; 6CNRS, UMR5535; 7Université Montpellier 2; 8Laboratoire de Biochimie, Centre Hospitalier Universitaire Lapeyronie; 9UMR 204 Prévention des malnutritions et des pathologies associées, Institut Universitaire de Recherche Clinique; 10Institut des Biomolécules Max Mousseron CNRS UMR5247 CC 1706, Université de Montpellier 2, Montpellier, France; 11Service d'Urologie, CHU Groupe Hospitalisation Carémeau; 12Service d'Urologie, Polyclinique Kennedy, Nîmes, France; and 13CHU Henri Mondor, Creteil, France

Tóm tắt

Abstract Increased de novo fatty acid (FA) synthesis is one hallmark of tumor cells, including prostate cancer. We present here our most recent results showing that lipid composition in human prostate cancer is characterized by an increased ratio of monounsaturated FA to saturated FA, compared with normal prostate, and evidence the overexpression of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) in human prostate cancer. As a new therapeutic strategy, we show that pharmacologic inhibition of SCD1 activity impairs lipid synthesis and results in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells, abrogates the growth of prostate tumor xenografts in nude mice, and confers therapeutic benefit on animal survival. We show that these changes in lipid synthesis are translated into the inhibition of the AKT pathway and that the decrease in concentration of phosphatidylinositol-3,4,5-trisphosphate might at least partially mediate this effect. Inhibition of SCD1 also promotes the activation of AMP-activated kinase and glycogen synthase kinase 3α/β, the latter on being consistent with a decrease in β-catenin activity and mRNA levels of various β-catenin growth-promoting transcriptional targets. Furthermore, we show that SCD1 activity is required for cell transformation by Ras oncogene. Together, our data support for the first time the concept of targeting the lipogenic enzyme SCD1 as a new promising therapeutic approach to block oncogenesis and prostate cancer progression. Mol Cancer Ther; 9(6); 1740–54. ©2010 AACR.

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Tài liệu tham khảo

Nelson, 2002, The program of androgen-responsive genes in neoplastic prostate epithelium, Proc Natl Acad Sci U S A, 18, 11890, 10.1073/pnas.182376299

Huggins, 1967, Endocrine-induced regression of cancers, Science, 3778, 1050, 10.1126/science.156.3778.1050

Feldman, 2001, The development of androgen-independent prostate cancer, Nat Rev Cancer, 1, 34, 10.1038/35094009

Warburg, 1956, On respiratory impairment in cancer cells, Science, 3215, 269, 10.1126/science.124.3215.269

Warburg, 1956, On the origin of cancer cells, Science, 3191, 309, 10.1126/science.123.3191.309

Vander Heiden, 2009, Understanding the Warburg effect: the metabolic requirements of cell proliferation, Science, 5930, 1029, 10.1126/science.1160809

Medes, 1953, Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro, Cancer Res, 1, 27

Mashima, 2009, De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy, Br J Cancer, 9, 1369, 10.1038/sj.bjc.6605007

Kuhajda, 2000, Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology, Nutrition, 3, 202, 10.1016/S0899-9007(99)00266-X

Kuhajda, 1994, Fatty acid synthesis: a potential selective target for antineoplastic therapy, Proc Natl Acad Sci U S A, 14, 6379, 10.1073/pnas.91.14.6379

Nagy, 2002, Lipid rafts and the local density of ErbB proteins influence the biological role of homo- and heteroassociations of ErbB2, J Cell Sci, 22, 4251, 10.1242/jcs.00118

Menendez, 2007, Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis, Nat Rev Cancer, 10, 763, 10.1038/nrc2222

Swinnen, 2006, Increased lipogenesis in cancer cells: new players, novel targets, Curr Opin Clin Nutr Metab Care, 4, 358, 10.1097/01.mco.0000232894.28674.30

Miyazaki, 2007, Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis, Cell Metab, 6, 484, 10.1016/j.cmet.2007.10.014

Patra, 2008, Dissecting lipid raft facilitated cell signaling pathways in cancer, Biochim Biophys Acta, 2, 182

Fu, Nicotinamide derivatives and their use as therapeutic agents

Sarruf, 2005, Cyclin D3 promotes adipogenesis through activation of peroxisome proliferator-activated receptor γ, Mol Cell Biol, 22, 9985, 10.1128/MCB.25.22.9985-9995.2005

Scaglia, 2008, Inhibition of stearoyl-CoA desaturase 1 expression in human lung adenocarcinoma cells impairs tumorigenesis, Int J Oncol, 4, 839

Wilson, 2001, Chain separation of monounsaturated fatty acid methyl esters by argentation thin-layer chromatography, J Chromatogr A, 1–2, 251, 10.1016/S0021-9673(00)01006-2

Abella, 2005, Cdk4 promotes adipogenesis through PPARγ activation, Cell Metab, 4, 239, 10.1016/j.cmet.2005.09.003

Fajas, 2002, The retinoblastoma-histone deacetylase 3 complex inhibits the peroxisome proliferator-activated receptor γ and adipocyte differentiation, Dev Cell, 903, 10.1016/S1534-5807(02)00360-X

Fajas, 2003, PPARγ controls cell proliferation and apoptosis in an RB-dependent manner, Oncogene, 27, 4186, 10.1038/sj.onc.1206530

Pizer, 2001, Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression, Prostate, 2, 102, 10.1002/pros.1052

Rossi, 2003, Fatty acid synthase expression defines distinct molecular signatures in prostate cancer, Mol Cancer Res, 10, 707

Davies, 1999, Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN, Cancer Res, 11, 2551

Kinkade, 2008, Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model, J Clin Invest, 9, 3051

de Souza, 2009, Role of the Akt pathway in prostate cancer, Curr Cancer Drug Targets, 2, 163, 10.2174/156800909787581006

Manning, 2007, AKT/PKB signaling: navigating downstream, Cell, 7, 1261, 10.1016/j.cell.2007.06.009

Kreisberg, 2004, Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer, Cancer Res, 15, 5232, 10.1158/0008-5472.CAN-04-0272

Shen, 2007, Pten inactivation and the emergence of androgen-independent prostate cancer, Cancer Res, 14, 6535, 10.1158/0008-5472.CAN-07-1271

Elstrom, 2004, Akt stimulates aerobic glycolysis in cancer cells, Cancer Res, 11, 3892, 10.1158/0008-5472.CAN-03-2904

Bauer, 2005, ATP citrate lyase is an important component of cell growth and transformation, Oncogene, 41, 6314, 10.1038/sj.onc.1208773

Van de Sande, 2002, Role of the phosphatidylinositol 3′-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells, Cancer Res, 3, 642

Bandyopadhyay, 2005, FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis, Oncogene, 34, 5389, 10.1038/sj.onc.1208555

Li, 1997, PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer, Science, 5308, 1943, 10.1126/science.275.5308.1943

Wymann, 2008, Lipid signalling in disease, Nat Rev Mol Cell Biol, 2, 162, 10.1038/nrm2335

Cross, 1995, Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B, Nature, 6559, 785, 10.1038/378785a0

Zheng, 2009, Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation, Mol Cell, 2, 237, 10.1016/j.molcel.2008.12.026

Rattan, 2005, 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, 47, 39582, 10.1074/jbc.M507443200

Jones, 2005, AMP-activated protein kinase induces a p53-dependent metabolic checkpoint, Mol Cell, 3, 283, 10.1016/j.molcel.2005.03.027

Hardie, 2007, AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy, Nat Rev Mol Cell Biol, 10, 774, 10.1038/nrm2249

Inoki, 2006, TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth, Cell, 5, 955, 10.1016/j.cell.2006.06.055

Long, 2006, AMP-activated protein kinase signaling in metabolic regulation, J Clin Invest, 7, 1776, 10.1172/JCI29044

Nadolski, 2007, Protein lipidation, FEBS J, 20, 5202, 10.1111/j.1742-4658.2007.06056.x

Takada, 2006, Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion, Dev Cell, 6, 791, 10.1016/j.devcel.2006.10.003

Voeller, 1991, v-rasH expression confers hormone-independent in vitro growth to LNCaP prostate carcinoma cells, Mol Endocrinol, 2, 209, 10.1210/mend-5-2-209

Gioeli, 2005, Signal transduction in prostate cancer progression, Clin Sci (Lond), 4, 293, 10.1042/CS20040329

Pearson, 2009, K-ras and Wnt signaling synergize to accelerate prostate tumorigenesis in the mouse, Cancer Res, 1, 94, 10.1158/0008-5472.CAN-08-2895

Yamashita, 2009, Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma, J Hepatol, 1, 100, 10.1016/j.jhep.2008.07.036

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Thông tin xuất bản

Molecular Cancer Therapeutics

Tập 9 Số 6

1740-1754

Thông tin tác giả