Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) ligands have been implicated in the growth inhibition and differentiation of certain human cancers with diverse tissue origin. In this study, expression of PPARγ in human hepatocellular carcinoma (HCC) and the effect of PPARγ ligands on HCC cells were investigated in vitro using Hep G2, HuH-7, KYN-1 and KYN-2 cell lines. All cell lines were found to express functionally active PPARγ and a marked growth inhibition was induced by thiazolidinedione ligands troglitazone, and pioglitazone as well as with its natural ligand 15-deoxy-Δ12,14-prostaglandin J2. The growth inhibitory effect was associated with a dose-dependent inhibition of DNA synthesis, cell cycle progression and α fetoprotein expression. © 2001 Cancer Research Campaign http://www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Aden DP, Fogel A, Plotkin S, Damjanov I and Knowels BB (1979) Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line. Nature 282: 615–616
Alam J and Cook JL (1990) Reporter genes: Application to the study of mammalian gene transcription. Anal Biochem 188: 245–254
Asou H, Verbeek W, Williamson E, Elstner E, Kubota T, Kamada N and Koeffler HP (1999) Growth inhibition of myeloid leukaemia cells by troglitazone a ligand for peroxisome proliferator activated receptor gamma and retinoids. Int J Oncol 15: 1027–1031
Auboeuf D, Rieusset J, Fajas L, Vallier P, Frering V, Riou JP, Stales B, Auwerx J, Laville M and Vidal H (1997) Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver-X receptor-α in humans: No alteration in adipose tissue of obese and NIDDM patients. Diabetes 46: 1319–1327
Brasier AR, Tate JE and Habener JF (1989) Optimised use of the firefly luciferase assay as a reporter gene in mammalian cell lines. Bio Techniques 7: 1116–1122
Brockman JA, Gupta RA and DuBois RN (1998) Activation of PPARγ leads to inhibition of anchorage independent growth of human colorectal cancer cells. Gastroenterology 115: 1049–1055
Butler R, Mitchell SH, Tindall DJ and Young CY (2000) Nonapoptotic cell death associated with S-phase arrest of prostate cancer cells via the peroxisome proliferator-activated receptor γ ligand 15-deoxy-delta 12, 14-postaglandin J2. Cell Growth Differ 11: 49–61
Chang T-H and Szabo E (2000) Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor γ in non-small cell lung cancer. Cancer Res 60: 1129–1138
Chawla A, Schwarz EJ, Dimaculangan DD and Lazar MA (1994) Peroxisome proliferator-activated receptor (PPAR) γ: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology 135: 798–800
Clay CE, Namen AM, Atsumi G, Willingham MC, High KP, Kute TE, Trimboli AJ, Fonteh AN, Dawson PA and Chilton FH (1999) Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells. Cancinogenesis 20: 1905–1911
Demetri GD, Fletcher CDM, Mueller E, Sarraf P, Naujoks R, Campbell N, Spiegelman BM and Singer S (1999) Induction of solid tumour differentiation by the peroxisome proliferator-activated receptor γ ligand troglitazone in patients with liposarcoma. Proc Natl Acad Sci USA 96: 3951–3956
Elbrecht A, Chen Y, Cullinan CA, Hayes N, Leibowitz MD, Moller DE and Berger J (1996) Molecular cloning, expression and characterisation of human peroxisome proliferator-activated receptors γ1 and γ2. Biochem Biophys Res Commun 224: 431–437
Elstner E, Muller C, Koshizuka K, Williamson EA, Park D, Asou H, Shintaku P, Said JW, Heber D and Koeffler HP (1998) Ligands for peroxisome proliferator-activated receptor γ and retenoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci USA 95: 8806–8811
Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM and Evans RM (1995) 15-deoxy-Δ12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ. Cell 83: 803–812
Galli A, Crabb D, Price D, Ceni E, Salzano R, Surrenti C and Casini A (2000) Peroxisome proliferator-activated receptor γ transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells. Hepatology 31: 101–108
Gelman L, Fruchart JC and Auwerx J (1999) An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs) and their roles in inflammation and cancer. Cell Mol Life Sci 55: 932–943
Guan YF, Zhang YH, Breyer RM, Davis L and Breyer MD (1999) Expression of peroxisome proliferator-activated receptor γ (PPARγ) in human transitional bladder cancer and its role in inducing cell death. Neoplasia 1: 330–339
He TC, Chan TA, Vogelstein B and Kinzler KW (1999) PPARγ is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 99: 335–345
Henney JE (1999) From the Food and Drug Administration: new type 2 diabetes drugs. JAMA 282: 932
Hirase N, Yanase T, Mu Y, Muta K, Umemura T, Takayanagi R and Nawata H (1999) Thiazolidinedione induces apoptosis and monocytic differentiation in the promyelocytic leukemia cell line HL60. Oncology 57 (S2): s17–s26
Hisatake JI, Ikezoe T, Carey M, Holden S, Tomoyasu S and Koeffler HP (2000) Down-regulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor γ in human prostate cancer. Cancer Res 60: 5494–5498
Jacobson LP, Zhang BC, Zhu YR, Wang JB, Wu Y, Zhang QN, Yu LY, Qian GS, Kuang SY, Li YF, Fang X, Zarba A, Chen B, Enger C, Davidson NE, Gorman MB, Gordon GB, Prochaska HJ, Egner PA, Groopman JD, Munoz A, Helzlsouer KJ and Kensler TW (1997) Oltipratz chemoprevention trial in Qidong, People’s Republic of China: study design and clinical outcomes. Cancer Epidemiol Biomarkers Prev 6: 257–265
Juge-Aubry C, Pernin A, Favez T, Burger AG, Wahlis W, Meier CA and Desvergne B (1997) DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. J Biol Chem 272: 2525–25259
Kawai K, Kawasaki-Tokui Y, Odaka T, Tsuruta F, Kazui M, Iwabuchi H, Nakamura T, Kinoshita T, Ikeda T, Yoshioka T, Komai T and Nakamura K (1997) Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice and dogs. ArzneimForsch/Drug Res 47: 356–368
Keelan JA, Sato TA, Marvin KW, Lander J, Gilmour RS and Mitchell MD (1999) 15-deoxy-delta (12, 14)-postaglandin J(2), a ligand for peroxisome proliferator-activated receptor γ, induces apoptosis in JEG3 choriocarcinoma cells. Biochem Biophys Res Commun 262: 579–585
Kitamura S, Miyazaki Y, Shinomura Y, Knodo S, Kanayama S and Matsuzawa Y (1999) Peroxisome proliferator-activated receptor γ induces growth arrest and differentiation markers of human colon cancer cells. Jpn J Cancer Res 90: 75–80
Kliewer SA and Willson TM (1998) The nuclear receptor PPARγ-bigger than fat. Curr Opin Genet Dev 8: 576–581
Kliewer SA, Umesono K, Noonan DJ, Heyman RA and Evans RM (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358: 771–774
Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC and Lehmann JM (1995) A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation. Cell 83: 813–819
Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble C, Devchand P, Wahli W, Willson TM, Lenhard JM and Lehmann JM (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptor α and γ. Proc Natl Acad Sci USA 94: 4318–4323
Kohlroser J, Mathai J, Reichheld J, Banner BF and Bonkovsky HL (2000) Hepatotoxicity due to troglitazone: Report of two cases and review of adverse events reported to the United States Food and Drug Administration. Am J Gastroenterol 95: 272–276
Kubota T, Koshizuka K, Williamson EA, Asou H, Said JW, Holden S, Miyoshi I and Koeffler HP (1998) Ligand for peroxisome proliferator-activated receptor γ (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res 58: 3344–3352
Lehmann JM, Moore LB, Smith-Oliver TA, Wilkinson WO, Willson TM and Kliewer SA (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma. J Biol Chem 270: 12953–12956
Lehmann JM, Lenhard JM, Oliver BB, Ringold GM and Kliewer SA (1997) Peroxisome proliferator-activated receptors α and γ are activated by indomethacin and other nonsteroidal anti-inflammatory drugs. J Biol Chem 272: 3406–3410
Maekawa T, Kinoshita Y, Matsushima Y, Okada A, Fukui H, Waki S, Kishi K, Kawanami C, Nakata H, Hassan S, Wakatsuki Y, Ota H, Amano K, Nakao M and Chiba T (1997) Helicobacter pylori induces proinflammatory cytokines and major histocompatibility complex class II antigen in mouse gastric epithelial cells. J Lab Clin Med 130: 442–449
Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schuetz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P and Evans RM (1995) The nuclear receptor superfamily: the second decade. Cell 83: 835–839
Marra F, Efsen E, Romanelli RG, Caligiuri A, Pastacaldi S, Batignani G, Bonacchi A, Caporale R, Laffi G, Pinzani M and Gentilini P (2000) Ligands of peroxisome proliferator-activated receptor g modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 119: 466–478
Miyahara T, Schrum L, Rippe R, Xiong S, Yee, Jr. HF, Motomura K, Anania FA, Willson TM and Tsukamoto H (2000) Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem 275: 35715–35722
Morrison RF and Farmer SR (1999) Role of PPARγ in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis. J Biol Chem 274: 17088–17097
Motomura W, Okumura T, Takahashi N, Obara T and Khogo Y (2000) Activation of peroxisome proliferator-activated receptor γ by troglitazone inhibits cell growth through the increase of p27Kip1 in human pancreatic carcinoma cells. Cancer Res 60: 5558–5564
Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ, Zhang M, Fletcher C, Singer S and Spiegelman BM (1998) Terminal differentiation of human breast cancer through PPAR γ. Mol Cell 1: 465–470
Mueller E, Smith M, Sarraf P, Kroll T, Aiyer A, Kaufman DS, Oh W, Demetri G, Figg WD, Zhou XP, Eng C, Spiegelman BM and Kantoff PW (2000) Effects of ligand activation of peroxisome proliferator-activated receptor γ in human prostate cancer. Proc Natl Acad Sci USA 97: 10990–10995
Muto Y, Morwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, Tanaka T, Tsurumi K, Okuno M, Tomita E, Nakamura T and Kojima T (Hepatoma Prevention Study Group) (1996) Prevention of second primary tumours by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. N Engl J Med 334: 1561–1567
Nakabayashi H, Taketa T, Miyano K, Yamane T and Sato J (1982) Growth of human hepatoma cell lines with differentiated functions in chemically defined medium. Cancer Res 42: 3858–3863
Niwa Y, Matsumura M, Shiratori Y, Imamura M, Kato N, Shina S, Okudaira T, Ikeda Y, Inoue T and Omata M (1996) Quantification of α-fetoprotein and albumin messenger RNAs in human hepatocellular carcinoma. Hepatology 23: 1384–1392
Nordeen SK (1988) Luciferase reporter gene vectors for analysis of promoters and enhancers. Bio Techniques 6: 454–457
Oka H, Yamamoto S, Kuroki T, Harihara S, Marumo T, Kim SR, Monna T, Kobayashi K and Tango T (1995) Prospective study of chemoprevention of hepatocellular carcinoma with Sho-saiko-to (TJ-9). Cancer 76: 743–749
Plosker GL and Faulds D (1999) Troglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs 57: 409–438
Sarraf P, Mueller E, Jones D, King FJ, DeAnglo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C and Spiegelman BM (1998) Differentiation and reversal of malignant changes in colon cancer through PPARγ. Nature Med 4: 1046–1052
Sato H, Ishihara S, Kawashima K, Moriyama N, Suetsugu H, Kazumori H, Okuyama T, Rumi MA, Fukuda R, Nagasue N and Kinoshita Y (2000) Expression of peroxisome proliferator-activated receptor (PPAR) γ in gastric cancer and inhibitory effects of PPARγ agonists. Br J Cancer 83: 1394–1400
Sugimura A, Kiriyama Y, Nochi H, Tsuchiya H, Tamoto K, Sakurada Y, Ui M and Tokumitsu Y (1999) Troglitazone suppress cell growth of myeloid leukemia cell lines by induction of p21WAF1/CIP1 cyclin-dependent kinase inhibitor. Biochem Biophys Res Commun 261: 833–837
Takahashi N, Okumura T, Motomura W, Fujimoto Y, Kawabata I and Kohgo Y (1999) Activation of PPARγ inhibits cell growth and apoptosis in human gastric cancer cells. FEBS Letter 455: 135–139
Tontonoz P, Hu E, Graves A, Budavari AI and Spiegelman BM (1994a) mPPARγ2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8: 1224–1234
Tontonoz P, Hu E and Spiegelman BM (1994b) Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79: 1147–1156
Tontonoz P, Singer S, Forman BM, Sarraf P, Fletcher JA, Fletcher C, Brun RP, Mueller E, Altiok S, Oppenheim H, Evans RM and Spiegelman BM (1997) Terminal differentiation of human liposarcoma cells by ligands for peroxisome proliferator-activated receptor γ and retinoid X receptor. Proc Natl Acad Sci USA 94: 237–241
Tsubouchi Y, Sano H, Kawahito Y, Mukai S, Yamada R, Kohno M, Inoue K, Hla T and Kondo M (2000) Inhibition of human lung cancer cell growth by the for peroxisome proliferator-activated receptor γ agonists through induction of apoptosis. Biochem Biophys Res Commun 270: 400–405
Vidal-Puig AJ, Considine RV, Jimenez-Linan M, Werman A, Pories WJ, Caro JF and Flier JS (1997) Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest 99: 2416–2422
Watkins PB and Whitcomb RW (1998) Hepatic dysfunction associated with troglitazone. N Engl J Med 388: 916–917
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 (1999) Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 3: 397–403
Yano H, Kojiro M and Nakashima T (1986) A new human hepatocellular carcinoma cell line (KYN-1) with a transformation to adenocarcinoma. In Vitro Cell Dev Biol 22: 637–646
Yano H, Maruiwa M, Murakami T, Fukuda K, Ito Y, Sugihara S and Kojiro M (1988) A new human pleomorphic hepatocellular carcinoma cell line, KYN-2. Acta Pathol Jpn 38: 953–966
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Rumi, M., Sato, H., Ishihara, S. et al. Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma. Br J Cancer 84, 1640–1647 (2001). https://doi.org/10.1054/bjoc.2001.1821
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.1821
Keywords
This article is cited by
-
Antineoplastic influence of nimesulide in chemically induced hepatocellular carcinoma by inhibition of DNA synthesis
Inflammopharmacology (2019)
-
Association of thiazolidinediones with gastric cancer in type 2 diabetes mellitus: a population-based case–control study
BMC Cancer (2013)
-
Involvement of PPARγ in the antitumoral action of cannabinoids on hepatocellular carcinoma
Cell Death & Disease (2013)
-
Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPARγ signaling pathway
Acta Pharmacologica Sinica (2009)
-
Genetic profiling of human cell lines used as in vitro model to study cardiovascular pathophysiology and pharmacotoxicology
Cell Biology and Toxicology (2009)