Heptadecanoic acid inhibits cell proliferation in PC‑9 non‑small‑cell lung cancer cells with acquired gefitinib resistance

Xu,Changzhi; Wu,Pengfei; Gao,Jiajia; Zhang,Lanlan; Ma,Tengfei; Ma,Bingbing; Yang,Shuai; Shao,Guojian; Yu,Yang; Huang,Xunduan; Yang,Xingyuan; Zhang,Buchang

doi:10.3892/or.2019.7130

Heptadecanoic acid inhibits cell proliferation in PC‑9 non‑small‑cell lung cancer cells with acquired gefitinib resistance

Authors:
- Changzhi Xu
- Pengfei Wu
- Jiajia Gao
- Lanlan Zhang
- Tengfei Ma
- Bingbing Ma
- Shuai Yang
- Guojian Shao
- Yang Yu
- Xunduan Huang
- Xingyuan Yang
- Buchang Zhang
View Affiliations

Affiliations: Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui 230601, P.R. China, Biotechnical Research Centre for Anhui Tianxiang Cereals, Oils and Foodstuffs Co., Ltd., Anhui University, Hefei, Anhui 230601, P.R. China, School of Life Sciences, Anhui University, Hefei, Anhui 230601, P.R. China
Published online on: April 18, 2019 https://doi.org/10.3892/or.2019.7130
Pages: 3499-3507

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Non‑small cell lung carcinomas (NSCLC) are common and are the leading cause of cancer‑associated mortality worldwide. Heptadecanoic acid (C17:0) is an odd‑chain saturated fatty acid. The effect of C17:0 on lung cancer has remained elusive. The present study examined the role of C17:0 in the PC‑9 NSCLC cell line and PC‑9 cells with acquired‑gefitinib resistance (PC‑9/GR) in vitro. Cell proliferation, migration, apoptosis, fatty acid composition and the activation of relevant signaling pathways were assessed. The results indicated that C17:0 significantly inhibited cell proliferation, and migration, while promoting apoptosis in PC‑9 and PC‑9/GR cells. Furthermore, C17:0 enhanced the cytotoxicity of gefitinib to PC‑9 and PC‑9/GR cells. Mechanistical analysis indicated that the activation of the phosphoinositide 3‑kinase/Akt signaling pathway was suppressed in C17:0‑treated PC‑9 and PC‑9/GR cells. Furthermore, the addition of C17:0 led to accumulation of 10‑cis‑heptadecenoic acid in NSCLC cells. Collectively, the present study demonstrated that C17:0 is an effective agent against NSCLC cells in vitro and the results may imply that the intake of C17:1 or C17:0‑rich food may be beneficial during the treatment of NSCLC.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Pao W and Chmielecki J: Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 10:760–774. 2010. View Article : Google Scholar : PubMed/NCBI
3	Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, et al: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 362:2380–2388. 2010. View Article : Google Scholar : PubMed/NCBI
4	Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, et al: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 31:3327–3334. 2013. View Article : Google Scholar : PubMed/NCBI
5	Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M and Eck MJ: The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA. 105:2070–2075. 2008. View Article : Google Scholar : PubMed/NCBI
6	Knott SRV, Wagenblast E, Khan S, Kim SY, Soto M, Wagner M, Turgeon MO, Fish L, Erard N, Gable AL, et al: Asparagine bioavailability governs metastasis in a model of breast cancer. Nature. 554:378–381. 2018. View Article : Google Scholar : PubMed/NCBI
7	Chen M, Wan L, Zhang J, Zhang J, Mendez L, Clohessy JG, Berry K, Victor J, Yin Q, Zhu Y, et al: Deregulated PP1alpha phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism. Nature communications. 9:1592018. View Article : Google Scholar : PubMed/NCBI
8	Chen M, Zhang J, Sampieri K, Clohessy JG, Mendez L, Gonzalez-Billalabeitia E, Liu XS, Lee YR, Fung J, Katon JM, et al: An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer. Nat Genet. 50:206–218. 2018. View Article : Google Scholar : PubMed/NCBI
9	Khaw KT, Friesen MD, Riboli E, Luben R and Wareham N: Plasma phospholipid fatty acid concentration and incident coronary heart disease in men and women: The EPIC-Norfolk prospective study. PLoS Med. 9:e10012552012. View Article : Google Scholar : PubMed/NCBI
10	Meikle PJ, Wong G, Barlow CK, Weir JM, Greeve MA, MacIntosh GL, Almasy L, Comuzzie AG, Mahaney MC, Kowalczyk A, et al: Plasma lipid profiling shows similar associations with prediabetes and type 2 diabetes. PLoS One. 8:e743412013. View Article : Google Scholar : PubMed/NCBI
11	Holman RT, Johnson SB and Kokmen E: Deficiencies of polyunsaturated fatty acids and replacement by nonessential fatty acids in plasma lipids in multiple sclerosis. Proc Natl Acad Sci USA. 86:4720–4724. 1989. View Article : Google Scholar : PubMed/NCBI
12	Fonteh AN, Cipolla M, Chiang J, Arakaki X and Harrington MG: Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer's disease. PLoS One. 9:e1005192014. View Article : Google Scholar : PubMed/NCBI
13	Adamska A and Rutkowska J: Odd- and branched-chain fatty acids in milk fat-characteristic and health properties. Postepy Hig Med Dosw (Online). 68:998–1007. 2014.(In Polish). View Article : Google Scholar : PubMed/NCBI
14	Yang Z, Liu S, Chen X, Chen H, Huang M and Zheng J: Induction of apoptotic cell death and in vivo growth inhibition of human cancer cells by a saturated branched-chain fatty acid, 13-methyltetradecanoic acid. Cancer Res. 60:505–509. 2000.PubMed/NCBI
15	Fukuzawa M, Yamaguchi R, Hide I, Chen Z, Hirai Y, Sugimoto A, Yasuhara T and Nakata Y: Possible involvement of long chain fatty acids in the spores of Ganoderma lucidum (Reishi Houshi) to its anti-tumor activity. Biol Pharm Bull. 31:1933–1937. 2008. View Article : Google Scholar : PubMed/NCBI
16	Fei SJ, Zhang XC, Dong S, Cheng H, Zhang YF, Huang L, Zhou HY, Xie Z, Chen ZH and Wu YL: Targeting mTOR to overcome epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small cell lung cancer cells. PLoS One. 8:e691042013. View Article : Google Scholar : PubMed/NCBI
17	Meng H, Shen Y, Shen J, Zhou F, Shen S and Das UN: Effect of n-3 and n-6 unsaturated fatty acids on prostate cancer (PC-3) and prostate epithelial (RWPE-1) cells in vitro. Lipids Health Dis. 12:1602013. View Article : Google Scholar : PubMed/NCBI
18	Gatenby RA and Gillies RJ: Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 4:891–899. 2004. View Article : Google Scholar : PubMed/NCBI
19	Zhan N, Li B, Xu X, Xu J and Hu S: Inhibition of FASN expression enhances radiosensitivity in human non-small cell lung cancer. Oncol Lett. 15:4578–4584. 2018.PubMed/NCBI
20	Ali A, Levantini E, Teo JT, Goggi J, Clohessy JG, Wu CS, Chen L, Yang H, Krishnan I, Kocher O, et al: Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non-small cell lung cancer. EMBO Mol Med. 10:e83132018. View Article : Google Scholar : PubMed/NCBI
21	Shen M, Tsai Y, Zhu R, Keng PC, Chen Y, Chen Y and Lee SO: FASN-TGF-beta1-PD-L1 axis contributes to the development of resistance to NK cell cytotoxicity of cisplatin-resistant lung cancer cells. Biochim Biophys Acta Mol Cell Biol Lipids. 1863:313–322. 2018. View Article : Google Scholar : PubMed/NCBI
22	Gouw AM, Eberlin LS, Margulis K, Sullivan DK, Toal GG, Tong L, Zare RN and Felsher DW: Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma. Proc Natl Acad Sci USA. 114:4300–4305. 2017. View Article : Google Scholar : PubMed/NCBI
23	Li G, Li M, Hu J, Lei R, Xiong H, Ji H, Yin H, Wei Q and Hu G: The microRNA-182-PDK4 axis regulates lung tumorigenesis by modulating pyruvate dehydrogenase and lipogenesis. Oncogene. 36:989–998. 2017. View Article : Google Scholar : PubMed/NCBI
24	Zhang C, Yu H, Ni X, Shen S and Das UN: Growth inhibitory effect of polyunsaturated fatty acids (PUFAs) on colon cancer cells via their growth inhibitory metabolites and fatty acid composition changes. PLoS One. 10:e01232562015. View Article : Google Scholar : PubMed/NCBI
25	Lin L, Ding Y, Wang Y, Wang Z, Yin X, Yan G, Zhang L, Yang P and Shen H: Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 66:432–448. 2017. View Article : Google Scholar : PubMed/NCBI
26	Malhotra A, Redberg RF and Meier P: Saturated fat does not clog the arteries: Coronary heart disease is a chronic inflammatory condition, the risk of which can be effectively reduced from healthy lifestyle interventions. Br J Sports Med. 51:1111–1112. 2017. View Article : Google Scholar : PubMed/NCBI
27	Liu Y, Cheng Y, Li J, Wang Y and Liu Y: Epoxy stearic acid, an oxidative product derived from oleic acid, induces cytotoxicity, oxidative stress, and apoptosis in HepG2 cells. J Agric Food Chem. 66:5237–5246. 2018. View Article : Google Scholar : PubMed/NCBI
28	Wongtangtintharn S, Oku H, Iwasaki H and Toda T: Effect of branched-chain fatty acids on fatty acid biosynthesis of human breast cancer cells. J Nutr Sci Vitaminol (Tokyo). 50:137–143. 2004. View Article : Google Scholar : PubMed/NCBI
29	Yin Y, Sui C, Meng F, Ma P and Jiang Y: The omega-3 polyunsaturated fatty acid docosahexaenoic acid inhibits proliferation and progression of non-small cell lung cancer cells through the reactive oxygen species-mediated inactivation of the PI3K/Akt pathway. Lipids Health Dis. 16:872017. View Article : Google Scholar : PubMed/NCBI
30	Igal RA: Roles of stearoylcoa desaturase-1 in the regulation of cancer cell growth, survival and tumorigenesis. Cancers (Basel). 3:2462–2477. 2011. View Article : Google Scholar : PubMed/NCBI
31	Noto A, Raffa S, De Vitis C, Roscilli G, Malpicci D, Coluccia P, Di Napoli A, Ricci A, Giovagnoli MR, Aurisicchio L, et al: Stearoyl-CoA desaturase-1 is a key factor for lung cancer-initiating cells. Cell Death Dis. 4:e9472013. View Article : Google Scholar : PubMed/NCBI
32	Ferrannini E, Barrett EJ, Bevilacqua S and DeFronzo RA: Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 72:1737–1747. 1983. View Article : Google Scholar : PubMed/NCBI
33	Nestel PJ, Straznicky N, Mellett NA, Wong G, De Souza DP, Tull DL, Barlow CK, Grima MT and Meikle PJ: Specific plasma lipid classes and phospholipid fatty acids indicative of dairy food consumption associate with insulin sensitivity. Am J Clin Nutr. 99:46–53. 2014. View Article : Google Scholar : PubMed/NCBI
34	Krachler B, Norberg M, Eriksson JW, Hallmans G, Johansson I, Vessby B, Weinehall L and Lindahl B: Fatty acid profile of the erythrocyte membrane preceding development of type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis. 18:503–510. 2008. View Article : Google Scholar : PubMed/NCBI
35	Maruyama C, Yoneyama M, Suyama N, Yoshimi K, Teramoto A, Sakaki Y, Suto Y, Takahashi K, Araki R, Ishizaka Y, et al: Differences in serum phospholipid fatty acid compositions and estimated desaturase activities between Japanese men with and without metabolic syndrome. J Atheroscler Thromb. 15:306–313. 2008. View Article : Google Scholar : PubMed/NCBI
36	Magnusdottir OK, Landberg R, Gunnarsdottir I, Cloetens L, Akesson B, Landin-Olsson M, Rosqvist F, Iggman D, Schwab U, Herzig KH, et al: Plasma alkylresorcinols C17:0/C21:0 ratio, a biomarker of relative whole-grain rye intake, is associated to insulin sensitivity: A randomized study. Eur J Clin Nutr. 68:453–458. 2014. View Article : Google Scholar : PubMed/NCBI
37	Forouhi NG, Koulman A, Sharp SJ, Imamura F, Kröger J, Schulze MB, Crowe FL, Huerta JM, Guevara M, Beulens JW, et al: Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: The EPIC-InterAct case-cohort study. Lancet Diabetes Endocrinol. 2:810–818. 2014. View Article : Google Scholar : PubMed/NCBI
38	Abdullah MM, Cyr A, Lépine MC, Labonté MÈ, Couture P, Jones PJ and Lamarche B: Recommended dairy product intake modulates circulating fatty acid profile in healthy adults: A multi-centre cross-over study. Br J Nutr. 113:435–444. 2015. View Article : Google Scholar : PubMed/NCBI
39	Finocchiaro C, Segre O, Fadda M, Monge T, Scigliano M, Schena M, Tinivella M, Tiozzo E, Catalano MG, Pugliese M, et al: Effect of n-3 fatty acids on patients with advanced lung cancer: A double-blind, placebo-controlled study. Br J Nutr. 108:327–333. 2012. View Article : Google Scholar : PubMed/NCBI
40	van der Meij BS, Langius JA, Spreeuwenberg MD, Slootmaker SM, Paul MA, Smit EF and van Leeuwen PA: Oral nutritional supplements containing n-3 polyunsaturated fatty acids affect quality of life and functional status in lung cancer patients during multimodality treatment: An RCT. Eur J Clin Nutr. 66:399–404. 2012. View Article : Google Scholar : PubMed/NCBI