Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Review Article

Targeting Key Metabolic Enzymes Involved in Lipid and Protein Biosyntheses for Breast Anticancer Therapies

Author(s): Mounia Guerram, Aida Mejda Hamdi, Lu-Yong Zhang and Zhenzhou Jiang

Volume 17, Issue 2, 2017

Page: [158 - 168] Pages: 11

DOI: 10.2174/1568009616666160603123014

Price: $65

Abstract

The evolution of genomic research enabled the genetic and molecular profiling of breast cancer and revealed the profound complexity and heterogeneity of this disease. Subtypes of breast cancer characterized by mutations and/or amplifications of some proto-oncogenes are associated with an increased rate of recurrence and poor prognosis. They represent a challenge in the clinic with limited arsenal to attack them. Nowadays, metabolic reprogramming is firmly established as a hallmark of cancer. An increased rate of lipid and protein syntheses in cancerous tissues, a direct consequence of alterations in key metabolic enzymes involved in these pathways, is now recognized as an important aspect of the rewired metabolism of neoplastic cells. Over the past several years, accumulating evidence has revealed that mutations or amplifications of some proto-oncogenes are primarily involved in this metabolic dysregulation. It is thus critically important to dissect the molecular mechanisms tumors use to link metabolic reprogramming with upstream altered signaling. In this article, we review the recent findings that support the importance of lipid and protein biosyntheses in breast tumorigenesis, discuss the crosstalk between growth factor signal transduction and key metabolic enzymes involved in these processes, and point out the potentials of developing new strategies and therapeutics to target these key parameters in order to help breast cancer patients by providing new therapeutic opportunities.

Keywords: Breast cancer, metabolism, proto-oncogenes, lipid, protein, targeted therapy.

Graphical Abstract
[1]
Porter, P.L. Global trends in breast cancer incidence and mortality. Salud Publica Mex., 2009, 51(Suppl. 2), s141-s146.
[2]
Hortobagyi, G.N.; de la Garza Salazar, J.; Pritchard, K.; Amadori, D.; Haidinger, R.; Hudis, C.A.; Khaled, H.; Liu, M.C.; Martin, M.; Namer, M. OShaughnessy, J.A.; Shen, Z.Z.; Albain, K.S. The global breast cancer burden: variations in epidemiology and survival. Clin. Breast Cancer, 2005, 6(5), 391-401.
[3]
Li, Y.; Luo, Q.; Yuan, L.; Miao, C.; Mu, X.; Xiao, W.; Li, J.; Sun, T.; Ma, E. JNK-dependent Atg4 upregulation mediates asperphenamate derivative BBP-induced autophagy in MCF-7 cells. Toxicol. Appl. Pharmacol., 2012, 263(1), 21-31.
[4]
Higgins, M.J.; Baselga, J. Targeted therapies for breast cancer. J. Clin. Invest., 2011, 121(10), 3797-3803.
[5]
Holliday, D.L.; Speirs, V. Choosing the right cell line for breast cancer research. Breast Cancer Res., 2011, 13(4), 215.
[6]
Kolibaba, K.S.; Druker, B.J. Protein tyrosine kinases and cancer. Biochim. Biophys. Acta, 1997, 1333(3), F217-F248.
[7]
Yarden, Y.; Sliwkowski, M.X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol., 2001, 2(2), 127-137.
[8]
Roskoski, R., Jr The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem. Biophys. Res. Commun., 2004, 319(1), 1-11.
[9]
Slamon, D.J.; Godolphin, W.; Jones, L.A.; Holt, J.A.; Wong, S.G.; Keith, D.E.; Levin, W.J.; Stuart, S.G.; Udove, J.; Ullrich, A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science, 1989, 244(4905), 707-712.
[10]
Yan, M.; Parker, B.A.; Schwab, R.; Kurzrock, R. HER2 aberrations in cancer: implications for therapy. Cancer Treat. Rev., 2014, 40(6), 770-780.
[11]
Nahta, R. Molecular mechanisms of trastuzumab-based treatment in HER2-overexpressing breast cancer. ISRN Oncol, 2012. 2012, 428062
[12]
García Rodríguez, J.; García Colmenero, C.; Clèries Soler, R.; Oleaga Sánchez, I. Rev. Esp. Salud Publica, 2010, 84(6), 843-850. [Five years survival of women diagnosed with breast cancer during the period 19971999 in Toledo-Centro and Mancha Area, Spain].
[13]
Jemal, A.; Siegel, R.; Ward, E.; Hao, Y.; Xu, J.; Thun, M. J. Cancer statistics, 2009. CA Cancer J. Clin., 2009, 59(4), 225-249.
[14]
Shi, J.M.; Bai, L.L.; Zhang, D.M.; Yiu, A.; Yin, Z.Q.; Han, W.L.; Liu, J.S.; Li, Y.; Fu, D.Y.; Ye, W.C. Saxifragifolin D induces the interplay between apoptosis and autophagy in breast cancer cells through ROS-dependent endoplasmic reticulum stress. Biochem. Pharmacol., 2013, 85(7), 913-926.
[15]
Pearce, N.J.; Yates, J.W.; Berkhout, T.A.; Jackson, B.; Tew, D.; Boyd, H.; Camilleri, P.; Sweeney, P.; Gribble, A.D.; Shaw, A.; Groot, P.H. The role of ATP citrate-lyase in the metabolic regulation of plasma lipids. Hypolipidaemic effects of SB-204990, a lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076. Biochem. J., 1998, 334(Pt 1), 113-119.
[16]
Medes, G.; Thomas, A.; Weinhouse, S. Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res., 1953, 13(1), 27-29.
[17]
Kutlu, B.; Cardozo, A.K.; Darville, M.I.; Kruhøffer, M.; Magnusson, N.; Ørntoft, T.; Eizirik, D.L. Discovery of gene networks regulating cytokine-induced dysfunction and apoptosis in insulin-producing INS-1 cells. Diabetes, 2003, 52(11), 2701-2719.
[18]
Furuta, E.; Okuda, H.; Kobayashi, A.; Watabe, K. Metabolic genes in cancer: their roles in tumor progression and clinical implications. Biochim. Biophys. Acta, 2010, 1805(2), 141-152.
[19]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5), 646-674.
[20]
Warburg, O. On the origin of cancer cells. Science, 1956, 123(3191), 309-314.
[21]
DeBerardinis, R.J.; Cheng, T. Qs next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene, 2010, 29(3), 313-324.
[22]
Baenke, F.; Peck, B.; Miess, H.; Schulze, A. Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Dis. Model. Mech., 2013, 6(6), 1353-1363.
[23]
Babic, I.; Anderson, E.S.; Tanaka, K.; Guo, D.; Masui, K.; Li, B.; Zhu, S.; Gu, Y.; Villa, G.R.; Akhavan, D.; Nathanson, D.; Gini, B.; Mareninov, S.; Li, R.; Camacho, C.E.; Kurdistani, S.K.; Eskin, A.; Nelson, S.F.; Yong, W.H.; Cavenee, W.K.; Cloughesy, T.F.; Christofk, H.R.; Black, D.L.; Mischel, P.S. EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer. Cell Metab., 2013, 17(6), 1000-1008.
[24]
Qie, S.; Chu, C.; Li, W.; Wang, C.; Sang, N. ErbB2 activation upregulates glutaminase 1 expression which promotes breast cancer cell proliferation. J. Cell. Biochem., 2014, 115(3), 498-509.
[25]
Guo, D.; Prins, R.M.; Dang, J.; Kuga, D.; Iwanami, A.; Soto, H.; Lin, K.Y.; Huang, T.T.; Akhavan, D.; Hock, M.B.; Zhu, S.; Kofman, A.A.; Bensinger, S.J.; Yong, W.H.; Vinters, H.V.; Horvath, S.; Watson, A.D.; Kuhn, J.G.; Robins, H.I.; Mehta, M.P.; Wen, P.Y.; DeAngelis, L.M.; Prados, M.D.; Mellinghoff, I.K.; Cloughesy, T.F.; Mischel, P.S. EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci. Signal., 2009, 2(101), ra82.
[26]
Cairns, R.A.; Harris, I.S.; Mak, T.W. Regulation of cancer cell metabolism. Nat. Rev. Cancer, 2011, 11(2), 85-95.
[27]
Ward, P.S.; Thompson, C.B. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell, 2012, 21(3), 297-308.
[28]
Son, J.; Lyssiotis, C.A.; Ying, H.; Wang, X.; Hua, S.; Ligorio, M.; Perera, R.M.; Ferrone, C.R.; Mullarky, E.; Shyh-Chang, N.; Kang, Y.; Fleming, J.B.; Bardeesy, N.; Asara, J.M.; Haigis, M.C.; DePinho, R.A.; Cantley, L.C.; Kimmelman, A.C. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature, 2013, 496(7443), 101-105.
[29]
Currie, E.; Schulze, A.; Zechner, R.; Walther, T.C.; Farese, R.V., Jr Cellular fatty acid metabolism and cancer. Cell Metab., 2013, 18(2), 153-161.
[30]
Griffiths, B.; Lewis, C.A.; Bensaad, K.; Ros, S.; Zhang, Q.; Ferber, E.C.; Konisti, S.; Peck, B.; Miess, H.; East, P.; Wakelam, M.; Harris, A.L.; Schulze, A. Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth. Cancer Metab., 2013, 1(1), 3.
[31]
Nieman, K.M.; Kenny, H.A.; Penicka, C.V.; Ladanyi, A.; Buell-Gutbrod, R.; Zillhardt, M.R.; Romero, I.L.; Carey, M.S.; Mills, G.B.; Hotamisligil, G.S.; Yamada, S.D.; Peter, M.E.; Gwin, K.; Lengyel, E. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med., 2011, 17(11), 1498-1503.
[32]
Santos, C.R.; Schulze, A. Lipid metabolism in cancer. FEBS J., 2012, 279(15), 2610-2623.
[33]
Kuhajda, F.P.; Jenner, K.; Wood, F.D.; Hennigar, R.A.; Jacobs, L.B.; Dick, J.D.; Pasternack, G.R. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc. Natl. Acad. Sci. USA, 1994, 91(14), 6379-6383.
[34]
Mashima, T.; Seimiya, H.; Tsuruo, T. De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br. J. Cancer, 2009, 100(9), 1369-1372.
[35]
Zaidi, N.; Swinnen, J.V.; Smans, K. ATP-citrate lyase: a key player in cancer metabolism. Cancer Res., 2012, 72(15), 3709-3714.
[36]
Chypre, M.; Zaidi, N.; Smans, K. ATP-citrate lyase: a mini-review. Biochem. Biophys. Res. Commun., 2012, 422(1), 1-4.
[37]
Kaelin, W.G., Jr; McKnight, S.L. Influence of metabolism on epigenetics and disease. Cell, 2013, 153(1), 56-69.
[38]
Witters, L.A.; Widmer, J.; King, A.N.; Fassihi, K.; Kuhajda, F. Identification of human acetyl-CoA carboxylase isozymes in tissue and in breast cancer cells. Int. J. Biochem., 1994, 26(4), 589-594.
[39]
Abu-Elheiga, L.; Almarza-Ortega, D.B.; Baldini, A.; Wakil, S.J. Human acetyl-CoA carboxylase 2. Molecular cloning, characterization, chromosomal mapping, and evidence for two isoforms. J. Biol. Chem., 1997, 272(16), 10669-10677.
[40]
Wakil, S.J.; Stoops, J.K.; Joshi, V.C. Fatty acid synthesis and its regulation. Annu. Rev. Biochem., 1983, 52, 537-579.
[41]
Oh, S.Y.; Lee, M.Y.; Kim, J.M.; Yoon, S.; Shin, S.; Park, Y.N.; Ahn, Y.H.; Kim, K.S. Alternative usages of multiple promoters of the acetyl-CoA carboxylase beta gene are related to differential transcriptional regulation in human and rodent tissues. J. Biol. Chem., 2005, 280(7), 5909-5916.
[42]
Menendez, J.A.; Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer, 2007, 7(10), 763-777.
[43]
Szutowicz, A.; Kwiatkowski, J.; Angielski, S. Lipogenetic and glycolytic enzyme activities in carcinoma and nonmalignant diseases of the human breast. Br. J. Cancer, 1979, 39(6), 681-687.
[44]
Bauer, D.E.; Hatzivassiliou, G.; Zhao, F.; Andreadis, C.; Thompson, C.B. ATP citrate lyase is an important component of cell growth and transformation. Oncogene, 2005, 24(41), 6314-6322.
[45]
Hatzivassiliou, G.; Zhao, F.; Bauer, D.E.; Andreadis, C.; Shaw, A.N.; Dhanak, D.; Hingorani, S.R.; Tuveson, D.A.; Thompson, C.B. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell, 2005, 8(4), 311-321.
[46]
Ma, J.; Yan, R.; Zu, X.; Cheng, J.M.; Rao, K.; Liao, D.F.; Cao, D. Aldo-keto reductase family 1 B10 affects fatty acid synthesis by regulating the stability of acetyl-CoA carboxylase-alpha in breast cancer cells. J. Biol. Chem., 2008, 283(6), 3418-3423.
[47]
Yahagi, N.; Shimano, H.; Hasegawa, K.; Ohashi, K.; Matsuzaka, T.; Najima, Y.; Sekiya, M.; Tomita, S.; Okazaki, H.; Tamura, Y.; Iizuka, Y.; Ohashi, K.; Nagai, R.; Ishibashi, S.; Kadowaki, T.; Makuuchi, M.; Ohnishi, S.; Osuga, J.; Yamada, N. Co-ordinate activation of lipogenic enzymes in hepatocellular carcinoma. Eur. J. Cancer, 2005, 41(9), 1316-1322.
[48]
Silva, S.D.; Perez, D.E.; Alves, F.A.; Nishimoto, I.N.; Pinto, C.A.; Kowalski, L.P.; Graner, E. ErbB2 and fatty acid synthase (FAS) expression in 102 squamous cell carcinomas of the tongue: correlation with clinical outcomes. Oral Oncol., 2008, 44(5), 484-490.
[49]
Ogino, S.; Nosho, K.; Meyerhardt, J.A.; Kirkner, G.J.; Chan, A.T.; Kawasaki, T.; Giovannucci, E.L.; Loda, M.; Fuchs, C.S. Cohort study of fatty acid synthase expression and patient survival in colon cancer. J. Clin. Oncol., 2008, 26(35), 5713-5720.
[50]
Dowling, S.; Cox, J.; Cenedella, R.J. Inhibition of fatty acid synthase by Orlistat accelerates gastric tumor cell apoptosis in culture and increases survival rates in gastric tumor bearing mice in vivo. Lipids, 2009, 44(6), 489-498.
[51]
Ueda, SM; Yap, KL; Davidson, B; Tian, Y; Murthy, V; Wang, TL Expression of fatty acid synthase depends on NAC1 and is associated with recurrent ovarian serous carcinomas. J. Oncol, 2010. 2010, 285191.
[52]
Pizer, E.S.; Jackisch, C.; Wood, F.D.; Pasternack, G.R.; Davidson, N.E.; Kuhajda, F.P. Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res., 1996, 56(12), 2745-2747.
[53]
Pizer, E.S.; Wood, F.D.; Heine, H.S.; Romantsev, F.E.; Pasternack, G.R.; Kuhajda, F.P. Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer. Cancer Res., 1996, 56(6), 1189-1193.
[54]
Li, J.N.; Mahmoud, M.A.; Han, W.F.; Ripple, M.; Pizer, E.S. Sterol regulatory element-binding protein-1 participates in the regulation of fatty acid synthase expression in colorectal neoplasia. Exp. Cell Res., 2000, 261(1), 159-165.
[55]
Swinnen, J.V.; Vanderhoydonc, F.; Elgamal, A.A.; Eelen, M.; Vercaeren, I.; Joniau, S.; Van Poppel, H.; Baert, L.; Goossens, K.; Heyns, W.; Verhoeven, G. Selective activation of the fatty acid synthesis pathway in human prostate cancer. Int. J. Cancer, 2000, 88(2), 176-179.
[56]
Yoon, S.; Lee, M.Y.; Park, S.W.; Moon, J.S.; Koh, Y.K.; Ahn, Y.H.; Park, B.W.; Kim, K.S. Up-regulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. J. Biol. Chem., 2007, 282(36), 26122-26131.
[57]
Kuhajda, F.P. Fatty acid synthase and cancer: new application of an old pathway. Cancer Res., 2006, 66(12), 5977-5980.
[58]
Menendez, J.A.; Mehmi, I.; Atlas, E.; Colomer, R.; Lupu, R. Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: Role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB. Int. J. Oncol., 2004, 24(3), 591-608.
[59]
Kumar-Sinha, C.; Ignatoski, K.W.; Lippman, M.E.; Ethier, S.P.; Chinnaiyan, A.M. Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis. Cancer Res., 2003, 63(1), 132-139.
[60]
Jensen, V.; Ladekarl, M.; Holm-Nielsen, P.; Melsen, F.; Soerensen, F.B. The prognostic value of oncogenic antigen 519 (OA-519) expression and proliferative activity detected by antibody MIB-1 in node-negative breast cancer. J. Pathol., 1995, 176(4), 343-352.
[61]
Milgraum, L.Z.; Witters, L.A.; Pasternack, G.R.; Kuhajda, F.P. Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma. Clin. Cancer Res., 1997, 3(11), 2115-2120.
[62]
Graff, J.R.; Zimmer, S.G. Translational control and metastatic progression: enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs. Clin. Exp. Metastasis, 2003, 20(3), 265-273.
[63]
Watkins, S.J.; Norbury, C.J. Translation initiation and its deregulation during tumorigenesis. Br. J. Cancer, 2002, 86(7), 1023-1027.
[64]
Dever, T.E. Translation initiation: adept at adapting. Trends Biochem. Sci., 1999, 24(10), 398-403.
[65]
Kozak, M. Initiation of translation in prokaryotes and eukaryotes. Gene, 1999, 234(2), 187-208.
[66]
Preiss, T.; Hentze, M.W. From factors to mechanisms: translation and translational control in eukaryotes. Curr. Opin. Genet. Dev., 1999, 9(5), 515-521.
[67]
Sheikh, M.S.; Fornace, A.J., Jr Regulation of translation initiation following stress. Oncogene, 1999, 18(45), 6121-6128.
[68]
Dancey, J.E. Therapeutic targets: MTOR and related pathways. Cancer Biol. Ther., 2006, 5(9), 1065-1073.
[69]
Deng, L.; Zhang, R.; Tang, F.; Li, C.; Xing, Y.Y.; Xi, T. Ursolic acid induces U937 cells differentiation by PI3K/Akt pathway activation. Chin. J. Nat. Med., 2014, 12(1), 15-19.
[70]
Castedo, M.; Ferri, K.F.; Kroemer, G. Mammalian target of rapamycin (mTOR): pro- and anti-apoptotic. Cell Death Differ., 2002, 9(2), 99-100.
[71]
Hay, N.; Sonenberg, N. Upstream and downstream of mTOR. Genes Dev., 2004, 18(16), 1926-1945.
[72]
Showkat, M; Beigh, MA Andrabi, KI mTOR signaling in protein translation regulation: implications in cancer genesis and therapeutic interventions. Mol. Biol. Int, 2014. 2014, 686984.
[73]
Morita, M.; Gravel, S.P.; Hulea, L.; Larsson, O.; Pollak, M.; St-Pierre, J.; Topisirovic, I. mTOR coordinates protein synthesis, mitochondrial activity and proliferation. Cell Cycle, 2015, 14(4), 473-480.
[74]
Fingar, D.C.; Blenis, J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene, 2004, 23(18), 3151-3171.
[75]
Ma, X.M.; Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol., 2009, 10(5), 307-318.
[76]
Wullschleger, S.; Loewith, R.; Hall, M.N. TOR signaling in growth and metabolism. Cell, 2006, 124(3), 471-484.
[77]
Guertin, D.A.; Sabatini, D.M. Defining the role of mTOR in cancer. Cancer Cell, 2007, 12(1), 9-22.
[78]
Polak, P.; Hall, M.N. mTOR and the control of whole body metabolism. Curr. Opin. Cell Biol., 2009, 21(2), 209-218.
[79]
Wang, X.; Proud, C.G. mTORC1 signaling: what we still dont know. J. Mol. Cell Biol., 2011, 3(4), 206-220.
[80]
Mamane, Y.; Petroulakis, E.; LeBacquer, O.; Sonenberg, N. mTOR, translation initiation and cancer. Oncogene, 2006, 25(48), 6416-6422.
[81]
Chen, Y.; Wei, H.; Liu, F.; Guan, J.L. Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) promotes breast cancer progression through enhancing glucose starvation-induced autophagy and Akt signaling. J. Biol. Chem., 2014, 289(2), 1164-1173.
[82]
Alessi, D.R.; Pearce, L.R.; García-Martínez, J.M. New insights into mTOR signaling: mTORC2 and beyond. Sci. Signal., 2009, 2(67), pe27.
[83]
Tanaka, K.; Babic, I.; Nathanson, D.; Akhavan, D.; Guo, D.; Gini, B.; Dang, J.; Zhu, S.; Yang, H.; De Jesus, J.; Amzajerdi, A.N.; Zhang, Y.; Dibble, C.C.; Dan, H.; Rinkenbaugh, A.; Yong, W.H.; Vinters, H.V.; Gera, J.F.; Cavenee, W.K.; Cloughesy, T.F.; Manning, B.D.; Baldwin, A.S.; Mischel, P.S. Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance. Cancer Discov., 2011, 1(6), 524-538.
[84]
Boroughs, L.K.; DeBerardinis, R.J. Metabolic pathways promoting cancer cell survival and growth. Nat. Cell Biol., 2015, 17(4), 351-359.
[85]
Qiu, B.; Simon, M.C. Oncogenes strike a balance between cellular growth and homeostasis. Semin. Cell Dev. Biol., 2015, 43, 3-10.
[86]
Desai, K.V.; Xiao, N.; Wang, W.; Gangi, L.; Greene, J.; Powell, J.I.; Dickson, R.; Furth, P.; Hunter, K.; Kucherlapati, R.; Simon, R.; Liu, E.T.; Green, J.E. Initiating oncogenic event determines gene-expression patterns of human breast cancer models. Proc. Natl. Acad. Sci. USA, 2002, 99(10), 6967-6972.
[87]
Guerram, M.; Jiang, Z.Z.; Yousef, B.A.; Hamdi, A.M.; Hassan, H.M.; Yuan, Z.Q.; Luo, H.W.; Zhu, X.; Zhang, L.Y. The potential utility of acetyltanshinone IIA in the treatment of HER2-overexpressed breast cancer: Induction of cancer cell death by targeting apoptotic and metabolic signaling pathways. Oncotarget, 2015, 6(26), 21865-21877.
[88]
Tennant, D.A.; Durán, R.V.; Gottlieb, E. Targeting metabolic transformation for cancer therapy. Nat. Rev. Cancer, 2010, 10(4), 267-277.
[89]
Sangwan, V.; Park, M. Receptor tyrosine kinases: role in cancer progression. Curr. Oncol., 2006, 13(5), 191-193.
[90]
Greulich, H.; Kaplan, B.; Mertins, P.; Chen, T.H.; Tanaka, K.E.; Yun, C.H.; Zhang, X.; Lee, S.H.; Cho, J.; Ambrogio, L.; Liao, R.; Imielinski, M.; Banerji, S.; Berger, A.H.; Lawrence, M.S.; Zhang, J.; Pho, N.H.; Walker, S.R.; Winckler, W.; Getz, G.; Frank, D.; Hahn, W.C.; Eck, M.J.; Mani, D.R.; Jaffe, J.D.; Carr, S.A.; Wong, K.K.; Meyerson, M. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc. Natl. Acad. Sci. USA, 2012, 109(36), 14476-14481.
[91]
Cizkova, M.; Susini, A.; Vacher, S.; Cizeron-Clairac, G.; Andrieu, C.; Driouch, K.; Fourme, E.; Lidereau, R.; Bièche, I. PIK3CA mutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgroups. Breast Cancer Res., 2012, 14(1), R28.
[92]
Janku, F.; Wheler, J.J.; Westin, S.N.; Moulder, S.L.; Naing, A.; Tsimberidou, A.M.; Fu, S.; Falchook, G.S.; Hong, D.S.; Garrido-Laguna, I.; Luthra, R.; Lee, J.J.; Lu, K.H.; Kurzrock, R. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J. Clin. Oncol., 2012, 30(8), 777-782.
[93]
Kechagioglou, P.; Papi, R.M.; Provatopoulou, X.; Kalogera, E.; Papadimitriou, E.; Grigoropoulos, P.; Nonni, A.; Zografos, G.; Kyriakidis, D.A.; Gounaris, A. Tumor suppressor PTEN in breast cancer: heterozygosity, mutations and protein expression. Anticancer Res., 2014, 34(3), 1387-1400.
[94]
Stern, H.M.; Gardner, H.; Burzykowski, T.; Elatre, W. OBrien, C.; Lackner, M.R.; Pestano, G.A.; Santiago, A.; Villalobos, I.; Eiermann, W.; Pienkowski, T.; Martin, M.; Robert, N.; Crown, J.; Nuciforo, P.; Bee, V.; Mackey, J.; Slamon, D.J.; Press, M.F. PTEN Loss Is Associated with Worse Outcome in HER2-Amplified Breast Cancer Patients but Is Not Associated with Trastuzumab Resistance. Clin. Cancer Res., 2015, 21(9), 2065-2074.
[95]
Ciriello, G.; Miller, M.L.; Aksoy, B.A.; Senbabaoglu, Y.; Schultz, N.; Sander, C. Emerging landscape of oncogenic signatures across human cancers. Nat. Genet., 2013, 45(10), 1127-1133.
[96]
Masui, K.; Cavenee, W.K.; Mischel, P.S. mTORC2 in the center of cancer metabolic reprogramming. Trends Endocrinol. Metab., 2014, 25(7), 364-373.
[97]
Hanai, J.; Doro, N.; Sasaki, A.T.; Kobayashi, S.; Cantley, L.C.; Seth, P.; Sukhatme, V.P. Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. J. Cell. Physiol., 2012, 227(4), 1709-1720.
[98]
Wang, C.; Xu, C.; Sun, M.; Luo, D.; Liao, D.F.; Cao, D. Acetyl-CoA carboxylase-alpha inhibitor TOFA induces human cancer cell apoptosis. Biochem. Biophys. Res. Commun., 2009, 385(3), 302-306.
[99]
Buzzai, M.; Bauer, D.E.; Jones, R.G.; Deberardinis, R.J.; Hatzivassiliou, G.; Elstrom, R.L.; Thompson, C.B. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation. Oncogene, 2005, 24(26), 4165-4173.
[100]
Yang, Y.A.; Han, W.F.; Morin, P.J.; Chrest, F.J.; Pizer, E.S. Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Exp. Cell Res., 2002, 279(1), 80-90.
[101]
Krycer, J.R.; Sharpe, L.J.; Luu, W.; Brown, A.J. The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrinol. Metab., 2010, 21(5), 268-276.
[102]
Furuta, E.; Pai, S.K.; Zhan, R.; Bandyopadhyay, S.; Watabe, M.; Mo, Y.Y.; Hirota, S.; Hosobe, S.; Tsukada, T.; Miura, K.; Kamada, S.; Saito, K.; Iiizumi, M.; Liu, W.; Ericsson, J.; Watabe, K. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res., 2008, 68(4), 1003-1011.
[103]
Laplante, M.; Sabatini, D.M. An emerging role of mTOR in lipid biosynthesis. Curr. Biol., 2009, 19(22), R1046-R1052.
[104]
Düvel, K.; Yecies, J.L.; Menon, S.; Raman, P.; Lipovsky, A.I.; Souza, A.L.; Triantafellow, E.; Ma, Q.; Gorski, R.; Cleaver, S.; Vander Heiden, M.G.; MacKeigan, J.P.; Finan, P.M.; Clish, C.B.; Murphy, L.O.; Manning, B.D. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell, 2010, 39(2), 171-183.
[105]
Lamming, D.W.; Sabatini, D.M. A Central role for mTOR in lipid homeostasis. Cell Metab., 2013, 18(4), 465-469.
[106]
Hagiwara, A.; Cornu, M.; Cybulski, N.; Polak, P.; Betz, C.; Trapani, F.; Terracciano, L.; Heim, M.H.; Rüegg, M.A.; Hall, M.N. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab., 2012, 15(5), 725-738.
[107]
Yuan, M.; Pino, E.; Wu, L.; Kacergis, M.; Soukas, A.A. Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. J. Biol. Chem., 2012, 287(35), 29579-29588.
[108]
Cybulski, N.; Polak, P.; Auwerx, J.; Rüegg, M.A.; Hall, M.N. mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc. Natl. Acad. Sci. USA, 2009, 106(24), 9902-9907.
[109]
Yao, Y.; Suraokar, M.; Darnay, B.G.; Hollier, B.G.; Shaiken, T.E.; Asano, T.; Chen, C.H.; Chang, B.H.; Lu, Y.; Mills, G.B.; Sarbassov, D.; Mani, S.A.; Abbruzzese, J.L.; Reddy, S.A. BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation. Sci. Signal., 2013, 6(257), ra2.
[110]
Jones, K.T.; Greer, E.R.; Pearce, D.; Ashrafi, K. Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS Biol., 2009, 7(3), e60.
[111]
Soukas, A.A.; Kane, E.A.; Carr, C.E.; Melo, J.A.; Ruvkun, G. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev., 2009, 23(4), 496-511.
[112]
Flavin, R.; Peluso, S.; Nguyen, P.L.; Loda, M. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol., 2010, 6(4), 551-562.
[113]
Li, S.; Qiu, L.; Wu, B.; Shen, H.; Zhu, J.; Zhou, L.; Gu, L.; Di, W. TOFA suppresses ovarian cancer cell growth in vitro and in vivo. Mol. Med. Rep., 2013, 8(2), 373-378.
[114]
Menendez, J.A. Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: molecular mechanisms and therapeutic perspectives. Biochim. Biophys. Acta, 2010, 1801(3), 381-391.
[115]
Menendez, J.A.; Vellon, L.; Mehmi, I.; Oza, B.P.; Ropero, S.; Colomer, R.; Lupu, R. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc. Natl. Acad. Sci. USA, 2004, 101(29), 10715-10720.
[116]
Grunt, T.W.; Wagner, R.; Grusch, M.; Berger, W.; Singer, C.F.; Marian, B.; Zielinski, C.C.; Lupu, R. Interaction between fatty acid synthase- and ErbB-systems in ovarian cancer cells. Biochem. Biophys. Res. Commun., 2009, 385(3), 454-459.
[117]
Zhao, Y.; Butler, E.B.; Tan, M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis., 2013, 4, e532.
[118]
Vazquez-Martin, A.; Colomer, R.; Brunet, J.; Menendez, J.A. Pharmacological blockade of fatty acid synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin by transcriptionally inhibiting HER2 super-expression occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells. Int. J. Oncol., 2007, 31(4), 769-776.
[119]
Pizer, E.S.; Thupari, J.; Han, W.F.; Pinn, M.L.; Chrest, F.J.; Frehywot, G.L.; Townsend, C.A.; Kuhajda, F.P. Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. Cancer Res., 2000, 60(2), 213-218.
[120]
Vazquez-Martin, A.; Ropero, S.; Brunet, J.; Colomer, R.; Menendez, J.A. Inhibition of Fatty Acid Synthase (FASN) synergistically enhances the efficacy of 5-fluorouracil in breast carcinoma cells. Oncol. Rep., 2007, 18(4), 973-980.
[121]
Funabashi, H.; Kawaguchi, A.; Tomoda, H.; Omura, S.; Okuda, S.; Iwasaki, S. Binding site of cerulenin in fatty acid synthetase. J. Biochem., 1989, 105(5), 751-755.
[122]
Menendez, J.A.; Lupu, R. Fatty acid synthase-catalyzed de novo fatty acid biosynthesis: from anabolic-energy-storage pathway in normal tissues to jack-of-all-trades in cancer cells. Arch. Immunol. Ther. Exp. (Warsz.), 2004, 52(6), 414-426.
[123]
Kuhajda, F.P. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition, 2000, 16(3), 202-208.
[124]
Uddin, S.; Siraj, A.K.; Al-Rasheed, M.; Ahmed, M.; Bu, R.; Myers, J.N.; Al-Nuaim, A.; Al-Sobhi, S.; Al-Dayel, F.; Bavi, P.; Hussain, A.R.; Al-Kuraya, K.S. Fatty acid synthase and AKT pathway signaling in a subset of papillary thyroid cancers. J. Clin. Endocrinol. Metab., 2008, 93(10), 4088-4097.
[125]
Lucas, K.H.; Kaplan-Machlis, B. Orlistata novel weight loss therapy. Ann. Pharmacother., 2001, 35(3), 314-328.
[126]
Kridel, S.J.; Axelrod, F.; Rozenkrantz, N.; Smith, J.W. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res., 2004, 64(6), 2070-2075.
[127]
Furuya, Y.; Akimoto, S.; Yasuda, K.; Ito, H. Apoptosis of androgen-independent prostate cell line induced by inhibition of fatty acid synthesis. Anticancer Res., 1997, 17(6D), 4589-4593.
[128]
Li, J.N.; Gorospe, M.; Chrest, F.J.; Kumaravel, T.S.; Evans, M.K.; Han, W.F.; Pizer, E.S. Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Res., 2001, 61(4), 1493-1499.
[129]
Pizer, E.S.; Wood, F.D.; Pasternack, G.R.; Kuhajda, F.P. Fatty acid synthase (FAS): a target for cytotoxic antimetabolites in HL60 promyelocytic leukemia cells. Cancer Res., 1996, 56(4), 745-751.
[130]
Knowles, L.M.; Axelrod, F.; Browne, C.D.; Smith, J.W. A fatty acid synthase blockade induces tumor cell-cycle arrest by down-regulating Skp2. J. Biol. Chem., 2004, 279(29), 30540-30545.
[131]
Harwood, H.J., Jr Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition. Expert Opin. Ther. Targets, 2005, 9(2), 267-281.
[132]
Chajès, V.; Cambot, M.; Moreau, K.; Lenoir, G.M.; Joulin, V. Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res., 2006, 66(10), 5287-5294.
[133]
Sola, M.M.; Oliver, F.J.; Salto, R.; Gutiérrez, M.; Vargas, A. Citrate inhibition of rat-kidney cortex phosphofructokinase. Mol. Cell. Biochem., 1994, 135(2), 123-128.
[134]
Chonan, T.; Oi, T.; Yamamoto, D.; Yashiro, M.; Wakasugi, D.; Tanaka, H.; Ohoka-Sugita, A.; Io, F.; Koretsune, H.; Hiratate, A. (4-Piperidinyl)-piperazine: a new platform for acetyl-CoA carboxylase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(23), 6645-6648.
[135]
Gu, Y.G.; Weitzberg, M.; Clark, R.F.; Xu, X.; Li, Q.; Zhang, T.; Hansen, T.M.; Liu, G.; Xin, Z.; Wang, X.; Wang, R.; McNally, T.; Zinker, B.A.; Frevert, E.U.; Camp, H.S.; Beutel, B.A.; Sham, H.L. Synthesis and structure-activity relationships of N-3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1- methylprop-2-ynylcarboxy derivatives as selective acetyl-CoA carboxylase 2 inhibitors. J. Med. Chem., 2006, 49(13), 3770-3773.
[136]
Harwood, H.J., Jr; Petras, S.F.; Shelly, L.D.; Zaccaro, L.M.; Perry, D.A.; Makowski, M.R.; Hargrove, D.M.; Martin, K.A.; Tracey, W.R.; Chapman, J.G.; Magee, W.P.; Dalvie, D.K.; Soliman, V.F.; Martin, W.H.; Mularski, C.J.; Eisenbeis, S.A. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J. Biol. Chem., 2003, 278(39), 37099-37111.
[137]
Shinde, P.; Srivastava, S.K.; Odedara, R.; Tuli, D.; Munshi, S.; Patel, J.; Zambad, S.P.; Sonawane, R.; Gupta, R.C.; Chauthaiwale, V.; Dutt, C. Synthesis of spiro[chroman-2,4-piperidin]-4-one derivatives as acetyl-CoA carboxylase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(3), 949-953.
[138]
Corbett, J.W.; Freeman-Cook, K.D.; Elliott, R.; Vajdos, F.; Rajamohan, F.; Kohls, D.; Marr, E.; Zhang, H.; Tong, L.; Tu, M.; Murdande, S.; Doran, S.D.; Houser, J.A.; Song, W.; Jones, C.J.; Coffey, S.B.; Buzon, L.; Minich, M.L.; Dirico, K.J.; Tapley, S.; McPherson, R.K.; Sugarman, E.; Harwood, H.J., Jr; Esler, W. Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2. Bioorg. Med. Chem. Lett., 2010, 20(7), 2383-2388.
[139]
Zu, X.Y.; Zhang, Q.H.; Liu, J.H.; Cao, R.X.; Zhong, J.; Yi, G.H.; Quan, Z.H.; Pizzorno, G. ATP citrate lyase inhibitors as novel cancer therapeutic agents. Recent Patents Anticancer. Drug Discov., 2012, 7(2), 154-167.
[140]
Vicier, C.; Dieci, M.V.; Arnedos, M.; Delaloge, S.; Viens, P.; Andre, F. Clinical development of mTOR inhibitors in breast cancer. Breast Cancer Res., 2014, 16(1), 203.
[141]
deGraffenried, L.A.; Friedrichs, W.E.; Russell, D.H.; Donzis, E.J.; Middleton, A.K.; Silva, J.M.; Roth, R.A.; Hidalgo, M. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin. Cancer Res., 2004, 10(23), 8059-8067.
[142]
Baselga, J.; Semiglazov, V.; van Dam, P.; Manikhas, A.; Bellet, M.; Mayordomo, J.; Campone, M.; Kubista, E.; Greil, R.; Bianchi, G.; Steinseifer, J.; Molloy, B.; Tokaji, E.; Gardner, H.; Phillips, P.; Stumm, M.; Lane, H.A.; Dixon, J.M.; Jonat, W.; Rugo, H.S. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J. Clin. Oncol., 2009, 27(16), 2630-2637.
[143]
Hudes, G.; Carducci, M.; Tomczak, P.; Dutcher, J.; Figlin, R.; Kapoor, A.; Staroslawska, E.; Sosman, J.; McDermott, D.; Bodrogi, I.; Kovacevic, Z.; Lesovoy, V.; Schmidt-Wolf, I.G.; Barbarash, O.; Gokmen, E. OToole, T.; Lustgarten, S.; Moore, L.; Motzer, R.J. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med., 2007, 356(22), 2271-2281.
[144]
Motzer, R.J.; Escudier, B.; Oudard, S.; Hutson, T.E.; Porta, C.; Bracarda, S.; Grünwald, V.; Thompson, J.A.; Figlin, R.A.; Hollaender, N.; Urbanowitz, G.; Berg, W.J.; Kay, A.; Lebwohl, D.; Ravaud, A. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet, 2008, 372(9637), 449-456.
[145]
Vignot, S.; Faivre, S.; Aguirre, D.; Raymond, E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann. Oncol., 2005, 16(4), 525-537.
[146]
Ansell, S.M.; Inwards, D.J.; Rowland, K.M., Jr; Flynn, P.J.; Morton, R.F.; Moore, D.F., Jr; Kaufmann, S.H.; Ghobrial, I.; Kurtin, P.J.; Maurer, M.; Allmer, C.; Witzig, T.E. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer, 2008, 113(3), 508-514.
[147]
Witzig, T.E.; Geyer, S.M.; Ghobrial, I.; Inwards, D.J.; Fonseca, R.; Kurtin, P.; Ansell, S.M.; Luyun, R.; Flynn, P.J.; Morton, R.F.; Dakhil, S.R.; Gross, H.; Kaufmann, S.H. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J. Clin. Oncol., 2005, 23(23), 5347-5356.
[148]
Mondesire, W.H.; Jian, W.; Zhang, H.; Ensor, J.; Hung, M.C.; Mills, G.B.; Meric-Bernstam, F. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin. Cancer Res., 2004, 10(20), 7031-7042.
[149]
Zhu, Y.; Zhang, X.; Liu, Y.; Zhang, S.; Liu, J.; Ma, Y.; Zhang, J. Antitumor effect of the mTOR inhibitor everolimus in combination with trastuzumab on human breast cancer stem cells in vitro and in vivo. Tumour Biol., 2012, 33(5), 1349-1362.
[150]
Singh, J.; Novik, Y.; Stein, S.; Volm, M.; Meyers, M.; Smith, J.; Omene, C.; Speyer, J.; Schneider, R.; Jhaveri, K.; Formenti, S.; Kyriakou, V.; Joseph, B.; Goldberg, J.D.; Li, X.; Adams, S.; Tiersten, A. Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer. Breast Cancer Res., 2014, 16(2), R32.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy