α‑linolenic acid inhibits human renal cell carcinoma cell proliferation through PPAR‑γ activation and COX‑2 inhibition

Yang,Lijun; Yuan,Jianlin; Liu,Liwen; Shi,Changhong; Wang,Longxin; Tian,Feng; Liu,Fei; Wang,He; Shao,Chen; Zhang,Qiang; Chen,Zhinan; Qin,Weijun; Wen,Weihong

doi:10.3892/ol.2013.1336

α‑linolenic acid inhibits human renal cell carcinoma cell proliferation through PPAR‑γ activation and COX‑2 inhibition

Authors:
- Lijun Yang
- Jianlin Yuan
- Liwen Liu
- Changhong Shi
- Longxin Wang
- Feng Tian
- Fei Liu
- He Wang
- Chen Shao
- Qiang Zhang
- Zhinan Chen
- Weijun Qin
- Weihong Wen
View Affiliations

Affiliations: Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China, Department of Ultrasound Diagnosis, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China, Laboratory Animals Center, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China, Department of Urology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA, Department of Immunology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
Published online on: May 8, 2013 https://doi.org/10.3892/ol.2013.1336
Pages: 197-202

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

ω‑3 fatty acids have potential anticancer effects, and consuming food rich in ω‑3 fatty acids reduces the human renal cell carcinoma (RCC) risk. However, the direct effect of ω‑3 fatty acids on RCC in vitro is unknown. In the present study, the effects of α‑linolenic acid (ALA), an ω‑3 fatty acid, were observed on cell proliferation in the RCC cell line OS‑RC‑2. The activity and gene expression levels of peroxisome proliferator‑activated receptor‑γ (PPAR‑γ) and cyclooxygenase‑2 (COX‑2) in the OS‑RC‑2 cells were measured by ELISA and real‑time RT‑PCR, respectively, following ALA treatment. ALA (20‑80 µM) dose‑dependently suppressed the proliferation of the OS‑RC‑2 cells. PPAR‑γ activity and gene expression were significantly increased by ALA at 20 and 40 µM. COX‑2 activity and gene expression levels were significantly decreased by ALA from 20 µM. Use of purely the PPAR‑γ agonist, rosiglitazone, decreased the proliferation of the OS‑RC‑2 cells, while ALA induced further suppression of cell proliferation in the presence of rosiglitazone. The COX‑2 inhibitor N‑(3‑Pyridyl)indomethacinamide induced further suppression of cell proliferation in the presence of rosiglitazone. N‑(3‑Pyridyl)indomethacinamide also suppressed the proliferation of the OS‑RC‑2 cells. In the presence of N‑(3‑Pyridyl)indomethacinamide, ALA and rosiglitazone further inhibited OS‑RC‑2 cell proliferation. In conclusion, ALA inhibits the cell proliferation of the OS‑RC‑2 human RCC cell line. PPAR‑γ activation and COX‑2 inhibition serve as two signaling pathways for the inhibitory effects of ALA on RCC cell proliferation.

View Figures

View References

1.	Motzer RJ, Bander NH and Nanus DM: Renal-cell carcinoma. N Engl J Med. 335:865–875. 1996. View Article : Google Scholar
2.	Rini BI, Rathmell WK and Godley P: Renal cell carcinoma. Curr Opin Oncol. 20:300–306. 2008. View Article : Google Scholar
3.	Rose DP and Connolly JM: Omega-3 fatty acids as cancer chemopreventive agents. Pharmacol Ther. 83:217–244. 1999. View Article : Google Scholar : PubMed/NCBI
4.	Rashidkhani B, Akesson A, Lindblad P and Wolk A: Major dietary patterns and risk of renal cell carcinoma in a prospective cohort of Swedish women. J Nutr. 135:1757–1762. 2005.PubMed/NCBI
5.	Wolk A, Larsson SC, Johansson JE and Ekman P: Long-term fatty fish consumption and renal cell carcinoma incidence in women. JAMA. 296:1371–1376. 2006. View Article : Google Scholar : PubMed/NCBI
6.	Spencer L, Mann C, Metcalfe M, Webb M, Pollard C, Spencer D, Berry D, Steward W and Dennison A: The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential. Eur J Cancer. 45:2077–2086. 2009. View Article : Google Scholar : PubMed/NCBI
7.	Wendel M and Heller AR: Anticancer actions of omega-3 fatty acids - current state and future perspectives. Anticancer Agents Med Chem. 9:457–470. 2009. View Article : Google Scholar : PubMed/NCBI
8.	Desvergne B and Wahli W: Peroxisome proliferator-activated receptors: Nuclear control of metabolism. Endocr Rev. 20:649–688. 1999.PubMed/NCBI
9.	Feige JN, Gelman L, Michalik L, Desvergne B and Wahli W: From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res. 45:120–159. 2006. View Article : Google Scholar
10.	Krishnan A, Nair SA and Pillai MR: Biology of PPAR gamma in cancer: a critical review on existing lacunae. Curr Mol Med. 7:532–540. 2007. View Article : Google Scholar : PubMed/NCBI
11.	Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, Devchand P, Wahli W, Willson TM, Lenhard JM and Lehmann JM: Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA. 94:4318–4323. 1997. View Article : Google Scholar
12.	Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, Kliewer SA and Milburn MV: Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell. 3:397–403. 1999. View Article : Google Scholar : PubMed/NCBI
13.	Lim K, Han C, Dai Y, Shen M and Wu T: Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2. Mol Cancer Ther. 8:3046–3055. 2009. View Article : Google Scholar : PubMed/NCBI
14.	Hashimoto Y, Kondo Y, Kimura G, Matsuzawa I, Sato S, Ishizaki M, Imura N, Akimoto M and Hara S: Cyclooxygenase-2 expression and relationship to tumour progression in human renal cell carcinoma. Histopathology. 44:353–359. 2004. View Article : Google Scholar : PubMed/NCBI
15.	Khan KN, Stanfield KM, Trajkovic D and Knapp DW: Expression of cyclooxygenase-2 in canine renal cell carcinoma. Vet Pathol. 38:116–119. 2001. View Article : Google Scholar : PubMed/NCBI
16.	Chen Q, Shinohara N, Abe T, Watanabe T, Nonomura K and Koyanagi T: Significance of COX-2 expression in human renal cell carcinoma cell lines. Int J Cancer. 108:825–832. 2004. View Article : Google Scholar : PubMed/NCBI
17.	Xin X, Yang S, Kowalski J and Gerritsen ME: Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem. 274:9116–9121. 1999. View Article : Google Scholar : PubMed/NCBI
18.	Rose DP and Connolly JM: Effects of fatty acids and inhibitors of eicosanoid synthesis on the growth of a human breast cancer cell line in culture. Cancer Res. 50:7139–7144. 1990.PubMed/NCBI
19.	Rose DP, Connolly JM, Rayburn J and Coleman M: Influence of diets containing eicosapentaenoic or docosahexaenoic acid on growth and metastasis of breast cancer cells in nude mice. J Natl Cancer Inst. 87:587–592. 1995. View Article : Google Scholar : PubMed/NCBI
20.	Karmali RA, Reichel P, Cohen LA, Terano T, Hirai A, Tamura Y and Yoshida S: The effects of dietary omega-3 fatty acids on the du-145 transplantable human prostatic tumor. Anticancer Res. 7:1173–1179. 1987.PubMed/NCBI
21.	Prentice RL and Sheppard L: Dietary fat and cancer: consistency of the epidemiologic data, and disease prevention that may follow from a practical reduction in fat consumption. Cancer Causes Control. 1:81–109. 1990. View Article : Google Scholar : PubMed/NCBI
22.	Stolzenberg-Solomon RZ, Pietinen P, Taylor PR, Virtamo J and Albanes D: Prospective study of diet and pancreatic cancer in male smokers. Am J Epidemiol. 155:783–792. 2002. View Article : Google Scholar : PubMed/NCBI
23.	Takezaki T, Inoue M, Kataoka H, Ikeda S, Yoshida M, Ohashi Y, Tajima K and Tominaga S: Diet and lung cancer risk from a 14-year population-based prospective study in Japan: with special reference to fish consumption. Nutr Cancer. 45:160–167. 2003.PubMed/NCBI
24.	Savage DB: PPAR gamma as a metabolic regulator: insights from genomics and pharmacology. Expert Rev Mol Med. 7:1–16. 2005. View Article : Google Scholar : PubMed/NCBI
25.	Knouff C and Auwerx J: Peroxisome proliferator-activated receptor-gamma calls for activation in moderation: lessons from genetics and pharmacology. Endocr Rev. 25:899–918. 2004. View Article : Google Scholar : PubMed/NCBI
26.	Picard F and Auwerx J: PPAR(gamma) and glucose homeostasis. Annu Rev Nutr. 22:167–197. 2002. View Article : Google Scholar : PubMed/NCBI
27.	Itoh T, Fairall L, Amin K, Inaba Y, Szanto A, Balint BL, Nagy L, Yamamoto K and Schwabe JW: Structural basis for the activation of PPARgamma by oxidized fatty acids. Nat Struct Mol Biol. 15:924–931. 2008. View Article : Google Scholar : PubMed/NCBI
28.	Edwards IJ and O’Flaherty JT: Omega-3 fatty acids and PPARgamma in cancer. PPAR Res. 2008:3580522008. View Article : Google Scholar : PubMed/NCBI
29.	Gani OA: Are fish oil omega-3 long-chain fatty acids and their derivatives peroxisome proliferator-activated receptor agonists? Cardiovasc Diabetol. 7:62008. View Article : Google Scholar : PubMed/NCBI
30.	Mansure JJ, Nassim R and Kassouf W: Peroxisome proliferator-activated receptor gamma in bladder cancer: a promising therapeutic target. Cancer Biol Ther. 8:6–15. 2009. View Article : Google Scholar : PubMed/NCBI
31.	Roman J: Peroxisome proliferator-activated receptor gamma and lung cancer biology: implications for therapy. J Investig Med. 56:528–533. 2008.PubMed/NCBI
32.	Voutsadakis IA: Peroxisome proliferator-activated receptor gamma (PPARgamma) and colorectal carcinogenesis. J Cancer Res Clin Oncol. 133:917–928. 2007. View Article : Google Scholar : PubMed/NCBI
33.	de Souza Pereira R: Selective cyclooxygenase-2 (COX-2) inhibitors used for preventing or regressing cancer. Recent Pat Anticancer Drug Discov. 4:157–163. 2009.
34.	Harris RE: Cyclooxygenase-2 (cox-2) blockade in the chemo-prevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology. 17:55–67. 2009. View Article : Google Scholar : PubMed/NCBI
35.	Fujimura T, Ohta T, Oyama K, Miyashita T and Miwa K: Cyclooxygenase-2 (COX-2) in carcinogenesis and selective COX-2 inhibitors for chemoprevention in gastrointestinal cancers. J Gastrointest Cancer. 38:78–82. 2007. View Article : Google Scholar : PubMed/NCBI
36.	Gilhooly EM and Rose DP: The association between a mutated ras gene and cyclooxygenase-2 expression in human breast cancer cell lines. Int J Oncol. 15:267–270. 1999.PubMed/NCBI
37.	Hussain T, Gupta S and Mukhtar H: Cyclooxygenase-2 and prostate carcinogenesis. Cancer Lett. 191:125–135. 2003. View Article : Google Scholar : PubMed/NCBI
38.	Lee KS, Lee HJ, Ahn KS and Kim SH, Nam D, Kim DK, Choi DY, Ahn KS, Lu J and Kim SH: Cyclooxygenase-2/prostaglandin e2 pathway mediates icariside II induced apoptosis in human PC-3 prostate cancer cells. Cancer Lett. 280:93–100. 2009. View Article : Google Scholar : PubMed/NCBI
39.	Sun WH, Chen GS, Ou XL, Yang Y, Luo C, Zhang Y, Shao Y, Xu HC, Xiao B, Xue YP, Zhou SM, Zhao QS and Ding GX: Inhibition of COX-2 and activation of peroxisome proliferator-activated receptor gamma synergistically inhibits proliferation and induces apoptosis of human pancreatic carcinoma cells. Cancer Lett. 275:247–255. 2009. View Article : Google Scholar
40.	Chen Q, Shinohara N, Abe T, Harabayashi T and Nonomura K: Impact of cyclooxygenase-2 gene expression on tumor invasiveness in a human renal cell carcinoma cell line. J Urol. 172:2153–2157. 2004. View Article : Google Scholar : PubMed/NCBI
41.	Hemmerlein B, Galuschka L, Putzer N, Zischkau S and Heuser M: Comparative analysis of COX-2, vascular endothelial growth factor and microvessel density in human renal cell carcinomas. Histopathology. 45:603–611. 2004. View Article : Google Scholar : PubMed/NCBI
42.	Bren-Mattison Y, Meyer AM, Van Putten V, Li H, Kuhn K, Stearman R, Weiser-Evans M, Winn RA, Heasley LE and Nemenoff RA: Antitumorigenic effects of peroxisome proliferator-activated receptor-gamma in non-small-cell lung cancer cells are mediated by suppression of cyclooxygenase-2 via inhibition of nuclear factor-kappaB. Mol Pharmacol. 73:709–717. 2008. View Article : Google Scholar
43.	Chêne G, Dubourdeau M, Balard P, Escoubet-Lozach L, Orfila C, Berry A, Bernad J, Aries MF, Charveron M and Pipy B: n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells. Biochim Biophys Acta. 1771:576–589. 2007.PubMed/NCBI
44.	Andrade LN, de Lima TM, Curi R and Castrucci AM: Toxicity of fatty acids on murine and human melanoma cell lines. Toxicol In Vitro. 19:553–560. 2005. View Article : Google Scholar : PubMed/NCBI
45.	Azevedo-Martins AK, Monteiro AP, Lima CL, Lenzen S and Curi R: Fatty acid-induced toxicity and neutral lipid accumulation in insulin-producing RINm5F cells. Toxicol In Vitro. 20:1106–1113. 2006. View Article : Google Scholar
46.	Otton R and Curi R: Toxicity of a mixture of fatty acids on human blood lymphocytes and leukaemia cell lines. Toxicol In Vitro. 19:749–755. 2005. View Article : Google Scholar : PubMed/NCBI