Effects of FASN on the growth of erlotinib-resistant cell line and its mechanism

Abstract

Abstract: AIM: To observe the effects of FASN on the proliferation and mechanism in erlotinib-resistant NSCLC cells. METHODS: Dected protein and mRNA expression levels of FASN by Western blot and quantitative RT-PCR in parental HCC827 cells and paired erlotinib-resistant HCC827-ER cells. The 5-days growth curve of HCC827-EP/ER were determined by SRB assay,after downregulating of FASN with small-interference RNA,Meanwhile, dected protein and mRNA levels of FoxO1 .Cell numbers in 5 days were measured by SRB assay after HCC827-ER transfecting with active form of FoxO1 adenovirus. RESULTS: The expression of FASN in HCC827-ER cells increased compared with paired HCC827-EP cells. And downregulation of FASN expression inhibited the growth of HCC827-ER cells (P<0.05). Protein and mRNA expression levels of FoxO1 increased after downregulating FASN.Upregulation of FoxO1 inhibited the growth of HCC827-ER cells.CONCLUSION: FASN expressed in a higher lever in HCC827-ER cells compared with HCC827-EP cells.Downregulation of FASN expression inhibited the growth of HCC827-ER cells,possibly through increased FoxO1 expression.

Key words: NSCLC, Erlotinib, FASN, FoxO1

CLC Number:

R965.2

CHEN Xi, LI Min, MA Zhuo, WU Dan-dan, NI Ping, ZHAI Su-lan, LI Ping, ZOU Mei-juan, WANG Xue-rong. Effects of FASN on the growth of erlotinib-resistant cell line and its mechanism[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(10): 1120-1125.

References 23

[1]	Pérez-Soler R, Chachoua A, Hammond L A, et al.Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer[J]. J Clin Oncol , 2004, 22(16): 3238-3247.
[2]	Pao W, Miller V A, Politi K A, et al.Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain[J]. PLoS medicine, 2005, 2(3): e73.
[3]	Chirala SS, Jayakumar A, Gu ZW, et al.Human fatty acid synthase: role of interdomain in the formation of catalytically active synthase dimer[J]. Proc Natl Acad Sci USA, 2001,98(6):3104-3108.
[4]	Smith S.The animal fatty acid synthase: one gene, one polypeptide, seven enzymes[J]. FASEB J, 1994, 8(15): 1248-1259.
[5]	Baron A, Migita T, Tang D, et al.Fatty acid synthase: a metabolic oncogene in prostate cancer[J]? J Cell Biochem , 2004, 91(1): 47-53.
[6]	Visca P, Sebastiani V, Botti C, et al.Fatty acid synthase (FAS) is a marker of increased risk of recurrence in lung carcinoma[J]. Anticancer Res, 2004, 24(6): 4169-4174.
[7]	Pizer E S, Pflug B R, Bova G S, et al.Increased fatty acid synthase as a therapeutic target in androgen‐independent prostate cancer progression[J]. Prostate, 2001, 47(2): 102-110.
[8]	Milgraum LZ, Witters LA, Pasternack G R, et al.Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma[J]. Clin Cancer Res, 1997, 3(11): 2115-2120.
[9]	Gansler TS, Hardman III W, Hunt DA, et al.Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival[J]. Human pathology, 1997, 28(6): 686-692.
[10]	Liu H, Liu Y, Zhang JT.A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction[J]. Mol Cancer Ther, 2008, 7(2): 263-270.
[11]	Menendez JA, Vellon L, Lupu R.Targeting fatty acid synthase-driven lipid rafts: a novel strategy to overcome trastuzumab resistance in breast cancer cells[J]. Medical hypotheses, 2005, 64(5): 997-1001.
[12]	Toulany M, Baumann M, Rodemann H P.Stimulated PI3K-AKT signaling mediated through ligand or radiation-induced EGFR depends indirectly, but not directly, on constitutive K-Ras activity[J]. Mol Cancer Res , 2007, 5(8): 863-872.
[13]	Matsuzaki H, Daitoku H, Hatta M, et al.Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation[J]. Proc Natl Acad Sci U S A , 2003, 100(20): 11285-11290.
[14]	Khuri FR, Sun SY.Elevated expression of eukaryotic translationinitiation factor 4E is associatedwith proliferation, invasion and acquiredresistance to erlotinib in lung cancer[J]. Cancer Biol Ther, 2012, 13(5): 272-280.
[15]	罗璇, 黄文斌, 翟溯澜, 等. 胰岛素受体底物 1 低表达促进头颈部鳞状细胞癌的侵袭转移[J]. 中国临床药理学与治疗学, 2012, 17(007): 744-750.
[16]	徐琳琳, 孙庆敏, 罗璇, 等. 金雀异黄素通过调控 miR-27a 及其靶基因对卵巢癌细胞 SKOV3 生长的影响[J]. 中国临床药理学与治疗学, 2012, 17(012): 1321-1326.
[17]	Kuhajda FP.Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology[J]. Nutrition, 2000, 16(3): 202-208.
[18]	Grunt TW, Wagner R, Grusch M, et al.Interaction between fatty acid synthase-and ErbB-systems in ovarian cancer cells[J]. Biochem Biophys Res Commun, 2009, 385(3): 454-459.
[19]	Wakil SJ.Fatty acid synthase, a proficient multifunctional enzyme[J]. Biochemistry, 1989, 28(11): 4523-4530.
[20]	Kuhajda FP.Fatty acid synthase and cancer: new application of an old pathway[J]. Cancer Res, 2006, 66(12): 5977-5980.
[21]	Shankar S, Chen Q, Srivastava RK.Inhibition of PI3K/AKT and MEK/ERK pathways act synergistically to enhance antiangiogenic effects of EGCG through activation of FOXO transcription factor[J]. J Mol Signal, 2008, 3:7.
[22]	Zhang X, Tang N, Hadden TJ, et al.Akt, FoxO and regulation of apoptosis[J]. Biochim Biophys Acta, 2011, 1813(11): 1978-1986.
[23]	Jones NP, Schulze A.Targeting cancer metabolism-aiming at a tumour's sweet-spot[J]. Drug Discov Today, 2012, 17(5): 232-241.