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Journal of Cancer Research and Clinical Oncology

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01.01.2016 | Original Article – Cancer Research

Loss of fatty acid synthase suppresses the malignant phenotype of colorectal cancer cells by down-regulating energy metabolism and mTOR signaling pathway

verfasst von: Ligong Chang, Peng Wu, Ravichandran Senthilkumar, Xiaoqiang Tian, Hui Liu, Xia Shen, Zijian Tao, Peilin Huang

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 1/2016

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Abstract

Purpose

Altered cellular metabolism has received increased attention as an important hallmark of cancer. Activation of FASN has been found to be involved in many human tumors. Despite extensive research in FASN function on cancer, the underlying mechanism is not entirely understood yet.

Methods

Cerulenin was used to suppress the FASN expression in human colorectal cancer cell lines (HT29 and LoVo). Expression of PI3K, Akt, p-Akt, mTOR, p-mTOR, FASN, and AZGP1 was measured using western blotting and qPCR. ATP and lactic acid were assessed to investigate the activation of energy metabolism. Cell cytotoxicity assay was studied by cell counting kit-8 assay. The capacity of cell proliferation and migration was investigated by clonogenic and invasion assay. Analysis of apoptosis and the cell cycle was detected by flow cytometry.

Results

We found that the expression of FASN was down-regulated, while the expression of PI3K, p-Akt, p-mTOR, and AZGP1 was down-regulated in HT29 and LoVo cells treated with FASN inhibitor. Proliferation was reduced in FASN inhibitor-treated cells, which is consistent with an increased apoptosis rate. Furthermore, the migration of FASN inhibitor-treated cells was decreased and the content of ATP and lactic acid was also dropped.

Conclusion

These findings suggest that inhibited FASN suppresses the malignant phenotype of colorectal cancer cells by down-regulating energy metabolism and mTOR signaling pathway. The results have paved the way to understand the relations of FASN, mTOR signaling pathway, and energy metabolism in colorectal cancer cells.

Alo’ PL, Visca P, Marci A, Mangoni A, Botti C, Di TU (1996) Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77(3):474–482PubMedCrossRef

Bandyopadhyay S, Zhan R, Wang Y, Pai SK, Hirota S, Hosobe S et al (2006) Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells. Cancer Res 66(11):5934–5940PubMedCrossRef

Bellacosa A, Kumar CC, Di CA, Testa JR (2005) Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 94:29–86PubMedCrossRef

Bongaerts GP, van Halteren HK, Verhagen CA, Wagener DJ (2006) Cancer cachexia demonstrates the energetic impact of gluconeogenesis in human metabolism. Med Hypotheses 67(5):1213–1222PubMedCrossRef

Chang L, Tian X, Lu Y, Jia M, Wu P, Huang P (2014) Alpha-2-glycoprotein 1(AZGP1) regulates biological behaviors of LoVo cells by down-regulating mTOR signaling pathway and endogenous fatty acid synthesis. PLoS One 9(6):e99254PubMedPubMedCentralCrossRef

Chiang CT, Way TD, Tsai SJ, Lin JK (2007) Diosgenin, a naturally occurring steroid, suppresses fatty acid synthase expression in HER2-overexpressing breast cancer cells through modulating Akt, mTOR and JNK phosphorylation. FEBS Lett 581(30):5735–5742PubMedCrossRef

Chiaradonna F, Moresco RM, Airoldi C, Gaglio D, Palorini R, Nicotra F et al (2012) From cancer metabolism to new biomarkers and drug targets. Biotechnol Adv 30(1):30–51PubMedCrossRef

Chuang HY, Chang YF, Hwang JJ (2011) Antitumor effect of orlistat, a fatty acid synthase inhibitor, is via activation of caspase-3 on human colorectal carcinoma-bearing animal. Biomed Pharmacother 65(4):286–292PubMedCrossRef

Dashnamoorthy R, Abermil N, Behesti A, Kozlowski P, Lansigan F, Kinlaw WB et al (2014) The lipid addiction of diffuse large B-cell lymphoma (DLBCL) and potential treatment strategies with novel fatty acid synthase (FASN) small molecule inhibitors. Blood 124(21):4490

DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7(1):11–20PubMedCrossRef

Deepa PR, Vandhana S, Jayanthi U, Krishnakumar S (2012) Therapeutic and toxicologic evaluation of anti-lipogenic agents in cancer cells compared with non-neoplastic cells. Basic Clin Pharmacol Toxicol 110:494–503PubMedCrossRef

Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL et al (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39:171–183PubMedPubMedCentralCrossRef

Epstein JI, Carmichael M, Partin AW (1995) OA-519 (fatty acid synthase) as an independent predictor of pathologic state in adenocarcinoma of the prostate. Urology 45(1):81–86PubMedCrossRef

Fako V, Wu X, Pflug B, Liu YJ, Zhang JT (2015) Repositioning proton pump inhibitors as anti-cancer drugs by targeting the thioesterase domain of human fatty acid synthase. J Med Chem 58(2):778–784PubMedPubMedCentralCrossRef

Flavin R, Peluso S, Nguyen PL, Loda M (2010) Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol 6(4):551–562PubMedPubMedCentralCrossRef

Francipane MG, Lagasse E (2014) mTOR pathway in colorectal cancer: an update. Oncotarget 5(1):49–66PubMedPubMedCentralCrossRef

Gago G, Diacovich L, Arabolaza A, Tsai SC, Gramajo H (2011) Fatty acid biosynthesis in actinomycetes. FEMS Microbiol Rev 35(3):475–497PubMedPubMedCentralCrossRef

Gansler TS, Hardman W 3rd, Hunt DA, Schaffel S, Hennigar RA (1997) Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival. Hum Pathol 28(6):686–692PubMedCrossRef

Garrido-Sanchez L, Vendrell J, Fernandez-Garcia D, Ceperuelo-Mallafre V, Chacon MR, Ocana-Wilhelmi L et al (2012) De novo lipogenesis in adipose tissue is associated with course of morbid obesity after bariatric surgery. PLoS One 7(2):e31280PubMedPubMedCentralCrossRef

Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis. Nat Rev Cancer 4(11):891–899PubMedCrossRef

Grube S, Dunisch P, Freitag D, Klausnitzer M, Sakr Y, Walter J et al (2014a) The mTOR inhibitor rapamycin synergizes with a fatty acid synthase inhibitor to induce cytotoxicity in ER/HER2-positive breast cancer cells. PLoS One 9(5):e97697CrossRef

Grube S, Dünisch P, Freitag D, Klausnitzer M, Sakr Y, Walter J et al (2014b) Overexpression of fatty acid synthase in human gliomas correlates with the WHO tumor grade and inhibition with Orlistat reduces cell viability and triggers apoptosis. J Neurooncol 118(2):277–287PubMedCrossRef

Hadad SM, Hardie DG (2014) Appleyard V, Thompson AM. Effects of metformin on breast cancer cell proliferation, the AMPK pathway and the cell cycle. Clin Transl Oncol 16(8):746–752PubMedCrossRef

Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70PubMedCrossRef

Hassan B, Akcakanat A, Holder AM, Meric-Bernstam F (2013) Targeting the PI3-kinase/Akt/mTOR signaling pathway. Surg Oncol Clin N Am 22(4):641–664PubMedCrossRef

Hilvo M, Denkert C, Lehtinen L, Muller B, Brockmoller S, Seppanen-Laakso T et al (2011) Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression. Cancer Res 71(9):3236–3245PubMedCrossRef

Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A et al (2012) The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485(7396):55–61PubMedPubMedCentralCrossRef

Huang P, Zhu S, Lu S, Dai Z, Jin Y (2000) An experimental study on cerulenin induced apoptosis of human colonic cancer cells. Zhonghua Bing Li Xue Za Zhi 29(2):115–118PubMed

Innocenzi D, Alò PL, Balzani A, Sebastiani V, Silipo V, La Torre G et al (2003) Fatty acid synthase expression in melanoma. J Cutan Pathol 30(1):23–28PubMedCrossRef

Janku F, Tsimberidou AM, Garrido-Laguna I, Wang X, Luthra R, Hong DS et al (2011) PIK3CA mutations in patients with advanced cancers treated with PI3K/Akt/mTOR axis inhibitors. Mol Cancer Ther 10(3):558–565PubMedPubMedCentralCrossRef

Jeong NY, Lee JS, Yoo KS, Oh S, Choe E, Lee HJ et al (2013) Fatty acid synthase inhibitor cerulenin inhibits topoisomerase I catalytic activity and augments SN-38-induced apoptosis. Apoptosis 18(2):226–237PubMedCrossRef

Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13(6):472–482PubMedCrossRef

Kuhajda FP (2000) Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 16(3):202–208PubMedCrossRef

Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD et al (1994) Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA 91(14):6379–6383PubMedPubMedCentralCrossRef

Kusakabe T, Nashimoto A, Honma K, Suzuki T (2002) Fatty acid synthase is highly expressed in carcinoma, adenoma and in regenerative epithelium and intestinal metaplasia of the stomach. Histopathology 40(1):71–79PubMedCrossRef

Li J, Kim SG, Blenis J (2014) Rapamycin: one drug, many effects. Cell Metab 19(3):373–379PubMedPubMedCentralCrossRef

Linehan WM, Rouault TA (2013) Molecular pathways: fumarate hydratase-deficient kidney cancer–targeting the Warburg effect in cancer. Clin Cancer Res 19(13):3345–3352PubMedPubMedCentralCrossRef

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25(4):402–408PubMedCrossRef

Long XH, Mao JH, Peng AF, Zhou Y, Huang SH, Liu ZL (2013) Tumor suppressive microRNA-424 inhibits osteosarcoma cell migration and invasion via targeting fatty acid synthase. Exp Ther Med 5(4):1048–1052PubMedPubMedCentral

Long QQ, Yi YX, Qiu J, Xu CJ, Huang PL (2014) Fatty acid synthase (FASN) levels in serum of colorectal cancer patients: correlation with clinical outcomes. Tumour Biol 35(4):3855–3859PubMedCrossRef

LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updates 11(1–2):32–50CrossRef

Mashima T, Seimiya H, Tsuruo T (2009) De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer 100(9):1369–1372PubMedPubMedCentralCrossRef

Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7(10):763–777PubMedCrossRef

Migita T, Ruiz S, Fornari A, Fiorentino M, Priolo C, Zadra G et al (2009) Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst 101(7):519–532PubMedPubMedCentralCrossRef

Milgraum LZ, Witters LA, Pasternack GR, Kuhajda FP (1997) Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma. Clin Cancer Res 3(11):2115–2120PubMed

Nosho K, Kawasaki T, Ohnishi M, Suemoto Y, Kirkner GJ, Zepf D et al (2008) PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. Neoplasia 10(6):534–541PubMedPubMedCentralCrossRef

Pelicano H, Martin DS, Xu RH, Huang P (2006a) Glycolysis inhibition for anticancer treatment. Oncogene 25(34):4633–4646PubMedCrossRef

Pelicano H, Xu RH, Du M, Feng L, Sasaki R, Carew JS et al (2006b) Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J Cell Biol 175(6):913–923PubMedPubMedCentralCrossRef

Piyathilake CJ, Frost AR, Manne U, Bell WC, Weiss H, Heimburger DC et al (2000) The expression of fatty acid synthase (FASE) is an early event in the development and progression of squamous cell carcinoma of the lung. Hum Pathol 31(9):1068–1073PubMedCrossRef

Pizer ES, Chrest FJ, DiGiuseppe JA, Han WF (1998) Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer Res 58(20):4611–4615PubMed

Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441(7092):437–443PubMedCrossRef

Rashid A, Pizer ES, Moga M, Milgraum LZ, Zahurak M, Pasternack GR et al (1997) Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. Am J Pathol 150(1):201–208PubMedPubMedCentral

Santolla MF, Lappano R, De Marco P, Pupo M, Vivacqua A, Sisci D et al (2012) G protein-coupled estrogen receptor mediates the up-regulation of fatty acid synthase induced by 17beta-estradiol in cancer cells and cancer-associated fibroblasts. J Biol Chem 287(52):43234–43245PubMedPubMedCentralCrossRef

Schulze A, Harris AL (2012) How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 491(7424):364–373PubMedCrossRef

Sebastiani V, Visca P, Botti C, Santeusanio G, Galati GM, Piccini V et al (2004) Fatty acid synthase is a marker of increased risk of recurrence in endometrial carcinoma. Gynecol Oncol 92(1):101–105PubMedCrossRef

Shiragami R, Murata S, Kosugi C, Tezuka T, Yamazaki M, Hirano A et al (2013) Enhanced antitumor activity of cerulenin combined with oxaliplatin in human colon cancer cells. Int J Oncol 43(2):431–438PubMed

Shurbaji MS, Kalbfleisch JH, Thurmond TS (1996) Immunohistochemical detection of a fatty acid synthase (OA-519) as a predictor of progression of prostate cancer. Hum Pathol 27(9):917–921PubMedCrossRef

Suva ML, Riggi N, Bernstein BE (2013) Epigenetic reprogramming in cancer. Science 339(6127):1567–1570PubMedCrossRef

Swierczynski J, Hebanowska A, Sledzinski T (2014) Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer. World J Gastroenterol 20(9):2279–2303PubMedPubMedCentralCrossRef

Swinnen JV, Roskams T, Joniau S, Van Poppel H, Oyen R, Baert L et al (2002) Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. Int J Cancer 98(1):19–22PubMedCrossRef

Thupari JN, Pinn ML, Kuhajda FP (2001) Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity[J]. Biochem Biophys Res Commun 285(2):217–223PubMedCrossRef

Vander HMG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033CrossRef

Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2(7):489–501PubMedCrossRef

Wang HQ, Altomare DA, Skele KL, Poulikakos PI, Kuhajda FP, Di Cristofano A et al (2005) Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells. Oncogene 24(22):3574–3582PubMedCrossRef

Warburg O (1956) On respiratory impairment in cancer cells. Science 124(3215):269–270PubMed

Ward C, Langdon SP, Mullen P, Harris AL, Harrison DJ, Supuran CT et al (2013) New strategies for targeting the hypoxic tumour microenvironment in breast cancer. Cancer Treat Rev 39(2):171–179PubMedCrossRef

Weiss L, Hoffmann GE, Schreiber R, Andres H, Fuchs E, Körber E et al (1986) Fatty-acid biosynthesis in man, a pathway of minor importance. Purification, optimal assay conditions, and organ distribution of fatty-acid synthase. Biol Chem Hoppe Seyler 367(9):905–912PubMedCrossRef

Wu X, Qin L, Fako V, Zhang JT (2014) Molecular mechanisms of fatty acid synthase (FASN)-mediated resistance to anti-cancer treatments. Adv Biol Regul 54:214–221PubMedCrossRef

Yap TA, Garrett MD, Walton MI, Raynaud F, de Bono JS, Workman P (2008) Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 8(4):393–412PubMedCrossRef

Zhan Y, Ginanni N, Tota MR, Wu M, Bays NW, Richon VM et al (2008) Control of cell growth and survival by enzymes of the fatty acid synthesis pathway in HCT-116 colon cancer cells. Clin Cancer Res 14(18):5735–5742PubMedCrossRef

Zhou W, Simpson PJ, McFadden JM, Townsend CA, Medghalchi SM, Vadlamudi A et al (2003) Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. Cancer Res 63(21):7330–7337PubMed

Titel: Loss of fatty acid synthase suppresses the malignant phenotype of colorectal cancer cells by down-regulating energy metabolism and mTOR signaling pathway
verfasst von: Ligong Chang
Peng Wu
Ravichandran Senthilkumar
Xiaoqiang Tian
Hui Liu
Xia Shen
Zijian Tao
Peilin Huang
Publikationsdatum: 01.01.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 1/2016
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-015-2000-8

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Loss of fatty acid synthase suppresses the malignant phenotype of colorectal cancer cells by down-regulating energy metabolism and mTOR signaling pathway

Abstract

Purpose

Methods

Results

Conclusion

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Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

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