Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Mechanism of Fatty Acid Synthase in Drug Tolerance Related to Epithelial-mesenchymal Transition of Breast Cancer

  • Li, Jun-Qin (Department of Anatomy, School of Basic and Forensic Medicine, Sichuan University) ;
  • Xue, Hui (Department of Anatomy, School of Basic and Forensic Medicine, Sichuan University) ;
  • Zhou, Lan (Department of Anatomy, School of Basic and Forensic Medicine, Sichuan University) ;
  • Dong, Li-Hua (Department of Anatomy, School of Basic and Forensic Medicine, Sichuan University) ;
  • Wei, Da-Peng (Department of Anatomy, School of Basic and Forensic Medicine, Sichuan University) ;
  • Li, Hua (Department of Anatomy, School of Basic and Forensic Medicine, Sichuan University)
  • Published : 2014.10.11
Download PDF
⟨ Previous Next ⟩

Abstract

Objective: The mechanism of action of fatty acid synthase (FASN) in drug tolerance of breast cancer cells with epithelial-mesenchymal transition (EMT) features was investigated. Methods: The breast cancer cell line MCF-7-MEK5 with stably occurring EMT and tumour necrosis factor-${\alpha}$ (TNF-${\alpha}$) tolerance was used as the experimental model, whereas MCF-7 acted as the control. Tumour cells were implanted into nude mice for in vivo analysis, and cerulenin was used as a FASN inhibitor. RT-PCR, real-time quantitative PCR and Western blot were employed to detect the expression of FASN, TNFR-1, TNFR-2, Wnt-1, ${\beta}$-catenin and cytC at the RNA and protein levels. Results: Compared with MCF-7, TNFR-1 expression in MCF-7-MEK5 was slightly changed, TNFR-2 was decreased, and FASN, Wnt-1, ${\beta}$-catenin and cytC were increased. The expression of Wnt-1 and ${\beta}$-catenin in MCF-7-MEK5 decreased after cerulenin treatment, whereas cytC expression increased. Conclusions: The important function of FASN in the drug tolerance of breast cancer may be due to the following mechanisms: FASN downregulated TNFR-2 expression through lipid rafts to make the cells less sensitive to TNF-${\alpha}$, and simultaneously activated the Wnt-$1/{\beta}$-catenin signalling pathway. Thus, cytC expression increased, which provided cells with anti-apoptotic capacity and induced drug tolerance.

Keywords

References

  1. Chen S, Denis CG, You ZB, et al (2001). Wnt-1 Signaling inhibits apoptosis by activating b-catenin/T cell factor-mediated transcription. J Cell Biol, 152, 87-96. https://doi.org/10.1083/jcb.152.1.87
  2. Chopra M, Riedel SS, Biehl M, et al (2013). Tumor necrosis factor receptor 2-dependent homeostasis of regulatory T cells as a player in TNF-induced experimental metastasis. Carcinogenesis, 34, 1296-303. https://doi.org/10.1093/carcin/bgt038
  3. Espinoza I, Hong PC, Busby R, Ruth L (2010). Inhibition of fatty acid synthase (FASN) sensitizes breast cancer cells to chemotherapy and disrupts the lipid rafts. Cancer Res, 70, p4-03-01. https://doi.org/10.1158/0008-5472.CAN-09-2257
  4. Fiorentino M, Zadra G, Palescandolo E, et al (2008). Overexpression of fatty acid synthase is associated with palmitoylation of Wnt-11 and cytoplasmic stabilization of b-catenin in prostate cancer. Lab Invest, 88, 1340-8. https://doi.org/10.1038/labinvest.2008.97
  5. Foster SS, De S, Johnson LK, et al (2012). Cell cycle- and DNA repair pathway-specific effects of apoptosis on tumor suppression. Proc Natl Acad Sci USA, 109, 9953-8. https://doi.org/10.1073/pnas.1120476109
  6. Gao FL, Song WG, Li WS, et al (2012). Correlation between expression of apoptosis modulators Smac and Cyt C and prognosis in esophageal squamous cell carcinoma. World Chinese J Digestology, 29, 226-8.
  7. Han RF, Ji X, Dong XG, et al (2013). An epigenetic mechanism underlying doxorubicin induced EMT in the human BGC-823 gastric cancer cell. Asian Pac J Cancer Prev, 15, 4271-4. https://doi.org/10.7314/APJCP.2014.15.10.4271
  8. Han XY, Wei B, Fang JF, et al (2013). Epithelial-mesenchymal transition associates with maintenance of stemness in spheroid-derived stem-like colon cancer cells. PLoS One, 8, 73341. https://doi.org/10.1371/journal.pone.0073341
  9. Heinlein C, Krepulat F, Lohler J, et al (2008). Mutant p53 (R270H) gain of function phenotype in a mouse model for oncogene-induced mammary carcinogenesis. Int J Cancer, 122, 1701-9.
  10. Hung CM, Kuo DH, Chou CH, et al (2011). Osthole suppresses hepatocyte growth factor (HGF)-induced epithelialmesenchymal transition via repression of the c-Met/Akt/mTOR pathway in human breast cancer cells. J Agric Food Chem, 5, 9683-90.
  11. Hüttemann M, Lee I, LI G, et al (2012). Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny: respiration, apoptosis, and human disease. Adv Exp Med Biol, 748, 237-64. https://doi.org/10.1007/978-1-4614-3573-0_10
  12. Kim MK, Maeng YI, Sung WJ, et al (2013). The differential expression of TGF-$\beta$1, ILK and wnt signaling inducing epithelial to mesenchymal transition in human renal fibrogenesis: an immunohistochemical study. Int J Clin Exp Pathol, 6, 1747-58.
  13. Kim SK, Foote MB, Huang L (2012). The targeted intracellular delivery of cytochrome C protein to tumors using lipidapolipoprotein nanoparticles. Biomaterials, 33, 3959-66. https://doi.org/10.1016/j.biomaterials.2012.02.010
  14. Liu H, Liu Y, Zhang JT (2008). A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction. Mol Cancer Ther, 7, 263-70. https://doi.org/10.1158/1535-7163.MCT-07-0445
  15. Liu Y, Du F, Chen W, ET AL (2013). Knockdown of dual specificity phosphatase 4 enhances the chemosensitivity of MCF-7 and MCF-7/ADR breast cancer cells to doxorubicin. Exp Cell Res, 319, 3140-9. https://doi.org/10.1016/j.yexcr.2013.08.023
  16. Mani SA, Guo W, Liao MJ, et al (2008). The epithelialmesenchymal transition generates cells with properties of stem cells. Cell, 133, 704-15. https://doi.org/10.1016/j.cell.2008.03.027
  17. Meena AS, Sharma A, Kumari R, et al (2013). Inherent and acquired resistance to paclitaxel in hepatocellular carcinoma: molecular events involved. PLoS One, 8, 61524. https://doi.org/10.1371/journal.pone.0061524
  18. Micalizzi DS, Farabaugh SM, Ford HL (2010). Epithelialmesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia, 15, 117-34. https://doi.org/10.1007/s10911-010-9178-9
  19. Mihara M, Erster S, Zaika A, et al (2003). p53 has a direct apoptogenic role at the mitochondria. Mol Cell, 11, 577-90. https://doi.org/10.1016/S1097-2765(03)00050-9
  20. Poonyachoti S, Deachapunya C (2012). Modulatory effects of phytoestrogens on the expression of Fas ligand and the release of cytochrome C in normal and cancerous endometrial cells. J Med Assoc Thai, 12, 105-12.
  21. Puig T, Aguilar H, Cufi S, et al (2011). A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti-HER2 drug-resistant cell lines. Breast Cancer Res, 13, 131. https://doi.org/10.1186/bcr3077
  22. Ramirez Alvarado M, Sanchez Roitz C (2012). El factor de necrosis tumoral-$\alpha$, la resistencia a la insulina, el metabolismo de lipoproteinas y la obesidad en humanos. Nutr Hosp, 27, 1751-7 (in Spanish).
  23. Sethi JK, Xu H, Uysal KT, et al (2000). Characterisation of receptor-specific TNFalpha functions in adipocytecell lines lacking type 1 and 2 TNF receptors. FEBS Lett, 469, 77-82. https://doi.org/10.1016/S0014-5793(00)01250-3
  24. Tian X, Liu Z, Niu B, et al (2011). E-cadherin/$\beta$-catenin complex and the epithelial barrier. J Biomed Biotechnol, 2011, 567305
  25. Urruticoechea A, Aguilar H, Cufi S, et al (2009). In vivo and in vitro evidence of antitumor activity of UCM-GI028 against trastuzumab-resistant breast cancer. Cancer Res, 69, 5079.
  26. Wang Y, Tian WX, Ma XF. (2013). Inhibitory effects of onion (Allium cepa L.) extract on proliferation of cancer cells and adipocytes via inhibiting fatty acid synthase. Asian Pac J Cancer Prev, 13, 5573-9. https://doi.org/10.7314/APJCP.2012.13.11.5573
  27. Wang ZW, Li YW, Kong DJ, et al (2009). Acquisition of Epithelial-Mesenchymal Transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of Notch signaling pathway. Cancer Res, 69, 2400-7. https://doi.org/10.1158/0008-5472.CAN-08-4312
  28. Xiao Y, Li H, Zhang J, et al (2011). TNF-$\alpha$/Fas-RIP-1-induced cell death signaling separates murine hematopoietic stem cells/progenitors into 2 distinct populations. Blood, 118, 6057-67. https://doi.org/10.1182/blood-2011-06-359448
  29. Xu TP, Shen H, Liu LX, Shu YQ (2013). Plumbagin from Plumbago zeylanica L induces apoptosis in human non-small cell lung cancer cell lines through NF- $\kappa$B inactivation. Asian Pac J Cancer Prev, 14, 2325-31. https://doi.org/10.7314/APJCP.2013.14.4.2325
  30. Zhao B, Li L, Cui K, et al (2011). Mechanisms of TRAIL and gemcitabine induction of pancreatic cancer cell apoptosis. Asian Pac J Cancer Prev, 12, 2675-8.
  31. Zhou CH, Nitschke AM, Xiong W, et al (2008). Proteomic analysis of tumor necrosis factor-$\alpha$ resistant human breast cancer cells reveals a MEK5/Erk5-mediated epithelialmesenchymal transition phenotype. Breast Cancer Res, 10, 105. https://doi.org/10.1186/bcr1990

Cited by

  1. Expression of Fatty Acid Synthase Negatively Correlates with PTEN and Predicts Peritoneal Dissemination of Human Gastric Cancer vol.16, pp.16, 2015, https://doi.org/10.7314/APJCP.2015.16.16.6851
  2. Upregulation of MEK5 by Stat3 promotes breast cancer cell invasion and metastasis vol.37, pp.1, 2016, https://doi.org/10.3892/or.2016.5256