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Molecular Cancer
Published in: Molecular Cancer 1/2014

Open Access 01-12-2014 | Research

Alpha-mangostin inhibits intracellular fatty acid synthase and induces apoptosis in breast cancer cells

Authors: Ping Li, Weixi Tian, Xiaofeng Ma

Published in: Molecular Cancer | Issue 1/2014

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Abstract

Background

Fatty acid synthase (FAS) has been proven over-expressed in human breast cancer cells and consequently, has been recognized as a target for breast cancer treatment. Alpha-mangostin, a natural xanthone found in mangosteen pericarp, has a variety of biological activities, including anti-cancer effect. In our previous study, alpha-mangostin had been found both fast-binding and slow-binding inhibitions to FAS in vitro. This study was designed to investigate the activity of alpha-mangostin on intracellular FAS activity in FAS over-expressed human breast cancer cells, and to testify whether the anti-cancer activity of alpha-mangostin may be related to its inhibitory effect on FAS.

Methods

We evaluated the cytotoxicity of alpha-mangostin in human breast cancer MCF-7 and MDA-MB-231 cells. Intracellular FAS activity was measured by a spectrophotometer at 340 nm of NADPH absorption. Cell Counting Kit assay was used to test the cell viability. Immunoblot analysis was performed to detect FAS expression level, intracellular fatty acid accumulation and cell signaling (FAK, ERK1/2 and AKT). Apoptotic effects were detected by flow cytometry and immunoblot analysis of PARP, Bax and Bcl-2. Small interfering RNA was used to down-regulate FAS expression and/or activity.

Results

Alpha-mangostin could effectively suppress FAS expression and inhibit intracellular FAS activity, and result in decrease of intracellular fatty acid accumulation. It could also reduce cell viability, induce apoptosis in human breast cancer cells, increase in the levels of the PARP cleavage product, and attenuate the balance between anti-apoptotic and pro-apoptotic proteins of the Bcl-2 family. Moreover, alpha-mangostin inhibited the phosphorylation of FAK. However, the active forms of AKT, and ERK1/2 proteins were not involved in the changes of FAS expression induced by alpha-mangostin.

Conclusions

Alpha-mangostin induced breast cancer cell apoptosis by inhibiting FAS, which provide a basis for the development of xanthone as an agent for breast cancer therapy.
Appendix
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Literature
1.
Wakil SJ: Fatty acid synthase, a proficient multifunctional enzyme. Biochemistry. 1989, 28: 4523-4530. 10.1021/bi00437a001CrossRefPubMed
2.
Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR: Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci U S A. 1994, 91: 6379-6383. 10.1073/pnas.91.14.6379PubMedCentralCrossRefPubMed
3.
Alò PL, Visca P, Trombetta G, Mangoni A, Lenti L, Monaco S, Botti C, Serpieri DE, Di Tondo U: Fatty acid synthase (FAS) predictive strength in poorly differentiated early breast carcinomas. Tumori. 1999, 85: 35-40.PubMed
4.
Alò PL, Visca P, Framarino ML, Botti C, Monaco S, Sebastiani V, Serpieri DE, Di Tondo U: Immunohistochemical study of fatty acid synthase in ovarian neoplasms. Oncol Rep. 2000, 7: 1383-1391.PubMed
5.
Shurbaji MS, Kalbfleisch JH, Thurmond TS: Immunohistochemical detection of a fatty acid synthase (OA-519) as a predictor of progression of prostate cancer. Hum Pathol. 1996, 27: 917-921. 10.1016/S0046-8177(96)90218-XCrossRefPubMed
6.
Weiss L, Hoffmann GE, Schreiber R, Andres H, Fuchs E, Körber E, Kolb HJ: 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. 1986, 367: 905-912. 10.1515/bchm3.1986.367.2.905CrossRefPubMed
7.
Ookhtens M, Kannan R, Lyon I, Baker N: Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am J Physiol. 1984, 247: R146-R153.PubMed
8.
Menendez JA, Lupu R: Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007, 7: 763-777. 10.1038/nrc2222CrossRefPubMed
9.
Kuhajda FP: Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition. 2000, 16: 202-208. 10.1016/S0899-9007(99)00266-XCrossRefPubMed
10.
Kuhajda FP: Fatty acid synthase and cancer: new application of an old pathway. Cancer Res. 2006, 66: 5977-5980. 10.1158/0008-5472.CAN-05-4673CrossRefPubMed
11.
Flavin R, Peluso S, Nguyen PL, Loda M: Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010, 6: 551-562. 10.2217/fon.10.11PubMedCentralCrossRefPubMed
12.
Akao Y, Nakagawa Y, Iinuma M, Nozawa Y: Anti-cancer effects of xanthones from pericarps of mangosteen. Int J Mol Sci. 2008, 9: 355-370. 10.3390/ijms9030355PubMedCentralCrossRefPubMed
13.
Matsumoto K, Akao Y, Yi H, Ohguchi K, Ito T, Tanaka T, Kobayashi E, Iinuma M, Nozawa Y: Preferential target is mitochondria in α-mangostin-induced apoptosis in human leukemia HL60 cells. Bioorg Med Chem. 2004, 12: 5799-5806. 10.1016/j.bmc.2004.08.034CrossRefPubMed
14.
Moongkarndi P, Kosem N, Kaslungka S, Luanratana O, Pongpan N, Neungton N: Antiproliferation, antioxidation and induction of apoptosis by Garcinia mangostana (mangosteen) on SKBR3 human breast cancer cell line. J Ethnopharmacol. 2004, 90: 161-166. 10.1016/j.jep.2003.09.048CrossRefPubMed
15.
Matsumoto K, Akao Y, Ohguchi K, Ito T, Tanaka T, Iinuma M, Nozawa Y: Xanthones induce cell-cycle arrest and apoptosis in human colon cancer DLD-1 cells. Bioorg Med Chem. 2005, 13: 6064-6069. 10.1016/j.bmc.2005.06.065CrossRefPubMed
16.
Johnson JJ, Petiwala SM, Syed DN, Rasmussen JT, Adhami VM, Siddiqui IA, Kohl AM, Mukhtar H: α-Mangostin, a xanthone from mangosteen fruit, promotes cell cycle arrest in prostate cancer and decreases xenograft tumor growth. Carcinogenesis. 2012, 33: 413-419. 10.1093/carcin/bgr291PubMedCentralCrossRefPubMed
17.
Quan X, Wang Y, Ma X, Liang Y, Tian W, Ma Q, Jiang H, Zhao Y: α-Mangostin induces apoptosis and suppresses differentiation of 3 T3-L1 cells via inhibiting fatty acid synthase. PLoS One. 2012, 7: e33376- 10.1371/journal.pone.0033376PubMedCentralCrossRefPubMed
18.
Lu YY, Chen TS, Qu JL, Pan WL, Sun L, Wei XB: Dihydroartemisinin (DHA) induces caspase-3-dependent apoptosis in human lung adenocarcinoma ASTC-a-1 cells. J Biomed Sci. 2009, 16: 16- 10.1186/1423-0127-16-16PubMedCentralCrossRefPubMed
19.
Menendez JA, Vellon L, Colomer R, Lupu R: Pharmacological and small interference RNA‒mediated inhibition of breast cancer‒associated fatty acid synthase (oncogenic antigen‒519) synergistically enhances Taxol (paclitaxel)‒induced cytotoxicity. Int J Cancer. 2005, 115: 19-35. 10.1002/ijc.20754CrossRefPubMed
20.
Migita T, Ruiz S, Fornari A, Fiorentino M, Priolo C, Zadra G, Inazuka F, Grisanzio C, Palescandolo E, Shin E, Fiore C, Xie W, Kung AL, Febbo PG, Subramanian A, Mucci L, Ma J, Signoretti S, Stampfer M, Hahn WC, Finn S, Loda M: Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst. 2009, 101: 519-532. 10.1093/jnci/djp030PubMedCentralCrossRefPubMed
21.
Little JL, Kridel SJ: Fatty acid synthase activity in tumor cells. Subcell Biochem. 2008, 49: 169-194. 10.1007/978-1-4020-8831-5_7CrossRefPubMed
22.
Yang YA, Han WF, Morin PJ, Chrest FJ, Pizer ES: Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Exp Cell Res. 2002, 279: 80-90. 10.1006/excr.2002.5600CrossRefPubMed
23.
Menendez JA, Lupu R, Colomer R: Targeting fatty acid synthase: potential for therapeutic intervention in her-2/neu-overexpressing breast cancer. Drug News Perspect. 2005, 18: 375-385. 10.1358/dnp.2005.18.6.927929CrossRefPubMed
24.
Puig T, Vázquez-Martín A, Relat J, Pétriz J, Menéndez JA, Porta R, Casals G, Marrero PF, Haro D, Brunet J, Colomer R: Fatty acid metabolism in breast cancer cells: differential inhibitory effects of epigallocatechin gallate (EGCG) and C75. Breast Cancer Res Treat. 2008, 109: 471-479. 10.1007/s10549-007-9678-5CrossRefPubMed
25.
Richardson RD, Smith JW: Novel antagonists of the thioesterase domain of human fatty acid synthase. Mol Cancer Ther. 2007, 6: 2120-2126. 10.1158/1535-7163.MCT-07-0187CrossRefPubMed
26.
Puig T, Turrado C, Benhamú B, Aguilar H, Relat J, Ortega-Gutiérrez S, Casals G, Marrero PF, Urruticoechea A, Haro D, López-Rodríguez ML, Colomer R: Novel inhibitors of fatty acid synthase with anticancer activity. Clin Cancer Res. 2009, 15: 7608-7615. 10.1158/1078-0432.CCR-09-0856CrossRefPubMed
27.
Hung SH, Shen KH, Wu CH, Liu CL, Shih YW: α-Mangostin suppresses PC-3 human prostate carcinoma cell metastasis by inhibiting matrix metalloproteinase-2/9 and urokinase-plasminogen expression through the JNK signaling pathway. J Agric Food Chem. 2009, 57: 1291-1298. 10.1021/jf8032683CrossRefPubMed
28.
Lee YB, Ko KC, Shi MD, Liao YC, Chiang TA, Wu PF, Shih YX, Shih YW: Alpha-mangostin, a novel dietary xanthone, suppresses TPA-mediated MMP-2 and MMP-9 expressions through the ERK signaling pathway in MCF-7 human breast adenocarcinoma cells. J Food Sci. 2010, 75: H13-H23. 10.1111/j.1750-3841.2009.01407.xCrossRefPubMed
29.
Shih YW, Chien ST, Chen PS, Lee JH, Wu SH, Yin LT: Alpha-mangostin suppresses phorbol 12-myristate 13-acetate-induced MMP-2/MMP-9 expressions via alphavbeta3 integrin/FAK/ERK and NF-kappaB signaling pathway in human lung adenocarcinoma A549 cells. Cell Biochem Biophys. 2010, 58: 31-44. 10.1007/s12013-010-9091-2CrossRefPubMed
30.
Watanapokasin R, Jarinthanan F, Nakamura Y, Sawasjirakij N, Jaratrungtawee A, Suksamrarn S: Effects of α-mangostin on apoptosis induction of human colon cancer. World J Gastroenterol. 2011, 17: 2086-2095. 10.3748/wjg.v17.i16.2086PubMedCentralCrossRefPubMed
31.
Shan T, Ma Q, Guo K, Liu J, Li W, Wang F, Wu E: Xanthones from mangosteen extracts as natural chemopreventive agents: potential anticancer drugs. Curr Mol Med. 2011, 11: 666-677. 10.2174/156652411797536679PubMedCentralCrossRefPubMed
32.
Menendez JA, Vellon L, Lupu R: Targeting fatty acid synthase-driven lipid rafts: a novel strategy to overcome trastuzumab resistance in breast cancer cells. Med Hypotheses. 2005, 64: 997-1001. 10.1016/j.mehy.2004.09.027CrossRefPubMed
33.
Jackowski S, Wang J, Baburina I: Activity of the phosphatidylcholine biosynthetic pathway modulates the distribution of fatty acids into glycerolipids in proliferating cells. Biochim Biophys Acta. 2000, 1483: 301-315. 10.1016/S1388-1981(99)00203-6CrossRefPubMed
34.
Lacroix M, Leclercq G: Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat. 2004, 83: 249-289. 10.1023/B:BREA.0000014042.54925.ccCrossRefPubMed
35.
Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F, Speed T, Spellman PT, DeVries S, Lapuk A, Wang NJ, Kuo WL, Stilwell JL, Pinkel D, Albertson DG, Waldman FM, McCormick F, Dickson RB, Johnson MD, Lippman M, Ethier S, Gazdar A, Gray JW: A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006, 10: 515-527. 10.1016/j.ccr.2006.10.008PubMedCentralCrossRefPubMed
36.
Menendez JA, 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-κB. Int J Oncol. 2004, 24: 591-608.PubMed
37.
Swinnen JV, Van Veldhoven PP, Timmermans L, De Schrijver E, Brusselmans K, Vanderhoydonc F, Van de Sande T, Heemers H, Heyns W, Verhoeven G: Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Biochem Biophys Res Commun. 2003, 302: 898-903. 10.1016/S0006-291X(03)00265-1CrossRefPubMed
38.
Wang HQ, Altomare DA, Skele KL, Poulikakos PI, Kuhajda FP, Di Cristofano A, Testa JR: Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells. Oncogene. 2005, 24: 3574-3582. 10.1038/sj.onc.1208463CrossRefPubMed
39.
Sul HS, Wang D: Nutritional and hormonal regulation of enzymes in fat synthesis: studies of fatty acid synthase and mitochondrial glycerol-3-phosphate acyltransferase gene transcription. Annu Rev Nutr. 1998, 18: 331-351. 10.1146/annurev.nutr.18.1.331CrossRefPubMed
40.
McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC: The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat Rev Cancer. 2005, 5: 505-515. 10.1038/nrc1647CrossRefPubMed
41.
Zhao J, Guan JL: Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev. 2009, 28: 35-49. 10.1007/s10555-008-9165-4CrossRefPubMed
42.
Luo M, Guan JL: Focal adhesion kinase: a prominent determinant in breast cancer initiation, progression and metastasis. Cancer Lett. 2010, 289: 127-139. 10.1016/j.canlet.2009.07.005PubMedCentralCrossRefPubMed
43.
Streuli CH, Edwards GM: Control of normal mammary epithelial phenotype by integrins. J Mammary Gland Biol Neoplasia. 1998, 3: 151-163. 10.1023/A:1018742822565CrossRefPubMed
44.
Pylayeva Y, Gillen KM, Gerald W, Beggs HE, Reichardt LF, Giancotti FG: Ras-and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J Clin Invest. 2009, 119: 252-266.PubMedCentralPubMed
45.
Hanahan D, Weinberg RA: The hallmarks of cancer. Cell. 2000, 100: 57-70. 10.1016/S0092-8674(00)81683-9CrossRefPubMed
46.
Boudreau N, Jones P: Extracellular matrix and integrin signalling: the shape of things to come. Biochem J. 1999, 339: 481-488. 10.1042/0264-6021:3390481PubMedCentralCrossRefPubMed
47.
Zaytseva YY, Rychahou PG, Gulhati P, Elliott VA, Mustain WC, O’Connor K, Morris AJ, Sunkara M, Weiss HL, Lee EY: Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res. 2012, 72: 1504-1517. 10.1158/0008-5472.CAN-11-4057PubMedCentralCrossRefPubMed
48.
Singletary SE, Connolly JL: Breast cancer staging: working with the sixth edition of the AJCC Cancer Staging Manual. CA Cancer J Clin. 2006, 56: 37-47. 10.3322/canjclin.56.1.37CrossRefPubMed
49.
Pedraza-Chaverri J, Cárdenas-Rodríguez N, Orozco-Ibarra M, Pérez-Rojas JM: Medicinal properties of mangosteen (Garcinia mangostana). Food Chem Toxicol. 2008, 46: 3227-3239. 10.1016/j.fct.2008.07.024CrossRefPubMed
50.
Chitchumroonchokchai C, Thomas-Ahner JM, Li J, Riedl KM, Nontakham J, Suksumrarn S, Clinton SK, Kinghorn AD, Failla ML: Anti-tumorigenicity of dietary α-mangostin in an HT-29 colon cell xenograft model and the tissue distribution of xanthones and their phase II metabolites. Mol Nutr Food Res. 2013, 57: 203-211. 10.1002/mnfr.201200539CrossRefPubMed
51.
Choi YH, Han SY, Kim YJ, Kim YM, Chin YW: Absorption, tissue distribution, tissue metabolism and safety of α-mangostin in mangosteen extract using mouse models. Food Chem Toxicol. 2014, 66: 140-146.CrossRefPubMed
52.
Li L, Brunner I, Han AR, Hamburger M, Kinghorn AD, Frye R, Butterweck V: Pharmacokinetics of α-mangostin in rats after intravenous and oral application. Mol Nutr Food Res. 2011, 55 (Suppl 1): S67-S74.CrossRefPubMed
Metadata
Title
Alpha-mangostin inhibits intracellular fatty acid synthase and induces apoptosis in breast cancer cells
Authors
Ping Li
Weixi Tian
Xiaofeng Ma
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-138

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