This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Han, S. Articles by Roman, J. Search for Related Content PubMed PubMed Citation Articles by Han, S. Articles by Roman, J.

Up-regulation of p21 Gene Expression by Peroxisome Proliferator-Activated Receptor in Human Lung Carcinoma Cells

¹ Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine and ² Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia; ³ Departments of Pathology, Neurosurgery, and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York; and ⁴ Atlanta Veterans Affairs Medical Center, Atlanta, Georgia

ABSTRACT

Purpose: The peroxisome proliferator-activated receptor (PPAR), a ligand-dependent transcription factor belonging to the family of nuclear receptors, has been implicated in the regulation of cell growth and differentiation although the exact mechanism(s) of this activity has not been elucidated. In this study, we explored the role of PPAR signaling on the control of gene expression of the cycle-dependent kinase inhibitor p21 in human lung carcinoma cells.

Experimental Design: Using several human lung carcinoma cell lines (small and non-small carcinoma cells), we assayed for cell growth inhibition and apoptosis induction. We also assayed for p21 mRNA and protein expression by reverse transcription-PCR, real-time reverse transcription-PCR, and Western blot analysis. Nuclear protein binding activities to three response elements located in the p21 promoter [nuclear factor (NF)-B, Sp1, and NF-interleukin 6 (IL6) CAAT/enhancer binding protein (C/EBP)] were measured by gel mobility shift assays. We used transient transfection assays with p21 promoter reporter gene constructs to determine the transcriptional regulation by PPAR ligands. Finally, by using p21 antisense oligonucleotides, we tested the link between PPAR activation and p21 signaling in cell growth inhibition assays and by Western blot analysis.

Results: We showed that the PPAR ligands PGJ2 and ciglitazone inhibit the growth and induce the apoptosis of several human lung carcinoma cell lines, whereas the PPAR agonist WY14643 has little effect. Treatment of lung carcinoma cells with the PPAR ligands PGJ2, ciglitazone, troglizaone, and GW1929 elevated p21 mRNA and protein levels and reduced cyclin D1 mRNA levels. These results were supported by transient transfection assays, which indicated that PPAR ligands increased p21 gene promoter activity in human lung carcinoma cells. In addition, p21 antisense oligonucleotides inhibited PPAR ligand-induced p21 protein expression and significantly blocked lung carcinoma cell growth inhibition induced by PPAR ligands. Finally, electrophoresis mobility shift experiments demonstrated that PPAR ligands increased the nuclear binding activities of Sp1 and NF-IL6 (C/EBP), two transcription factors with regulatory elements in the promoter region of the p21 gene.

Conclusion: PPAR ligands inhibit human lung carcinoma cell growth and induce apoptosis by stimulating the cyclin-dependent kinase inhibitor p21 and by reducing cyclin D1 gene expression. The induction of p21 gene expression by PPAR ligands may be mediated through increased Sp1- and NF-IL6 (C/EBP)-dependent transcriptional activation. These observations unveil a mechanism for p21 gene regulation in lung carcinoma that represents a potential target for therapy.

This article has been cited by other articles:

				S. Han, X. Sun, J. D. Ritzenthaler, and J. Roman Fish Oil Inhibits Human Lung Carcinoma Cell Growth by Suppressing Integrin-Linked Kinase Mol. Cancer Res., January 1, 2009; 7(1): 108 - 117. [Abstract] [Full Text] [PDF]

				D Bonofiglio, H Qi, S Gabriele, S Catalano, S Aquila, M Belmonte, and S Ando Peroxisome proliferator-activated receptor {gamma} inhibits follicular and anaplastic thyroid carcinoma cells growth by upregulating p21Cip1/WAF1 gene in a Sp1-dependent manner Endocr. Relat. Cancer, June 1, 2008; 15(2): 545 - 557. [Abstract] [Full Text] [PDF]

				W. Xia, S. Nagase, A. G. Montia, S. M. Kalachikov, M. Keniry, T. Su, L. Memeo, H. Hibshoosh, and R. Parsons BAF180 Is a Critical Regulator of p21 Induction and a Tumor Suppressor Mutated in Breast Cancer Cancer Res., March 15, 2008; 68(6): 1667 - 1674. [Abstract] [Full Text] [PDF]

				K. Y. Kim, J. H. Ahn, and H. G. Cheon Apoptotic Action of Peroxisome Proliferator-Activated Receptor-{gamma} Activation in Human Non Small-Cell Lung Cancer Is Mediated via Proline Oxidase-Induced Reactive Oxygen Species Formation Mol. Pharmacol., September 1, 2007; 72(3): 674 - 685. [Abstract] [Full Text] [PDF]

				F.-S. Chou, P.-S. Wang, S. Kulp, and J. J. Pinzone Effects of Thiazolidinediones on Differentiation, Proliferation, and Apoptosis Mol. Cancer Res., June 1, 2007; 5(6): 523 - 530. [Abstract] [Full Text] [PDF]

				H.-J. Kim, J.-Y. Kim, Z. Meng, L. H. Wang, F. Liu, T. P. Conrads, T. R. Burke, T. D. Veenstra, and W. L. Farrar 15-Deoxy-{Delta}12,14-Prostaglandin J2 Inhibits Transcriptional Activity of Estrogen Receptor-{alpha} via Covalent Modification of DNA-Binding Domain Cancer Res., March 15, 2007; 67(6): 2595 - 2602. [Abstract] [Full Text] [PDF]

				A. von Knethen, M. Soller, N. Tzieply, A. Weigert, A. M. Johann, C. Jennewein, R. Kohl, and B. Brune PPAR{gamma}1 attenuates cytosol to membrane translocation of PKC{alpha} to desensitize monocytes/macrophages J. Cell Biol., February 26, 2007; 176(5): 681 - 694. [Abstract] [Full Text] [PDF]

				J.-S. Annicotte, I. Iankova, S. Miard, V. Fritz, D. Sarruf, A. Abella, M.-L. Berthe, D. Noel, A. Pillon, F. Iborra, et al. Peroxisome Proliferator-Activated Receptor {gamma} Regulates E-Cadherin Expression and Inhibits Growth and Invasion of Prostate Cancer. Mol. Cell. Biol., October 1, 2006; 26(20): 7561 - 7574. [Abstract] [Full Text] [PDF]

				M. A. Peraza, A. D. Burdick, H. E. Marin, F. J. Gonzalez, and J. M. Peters The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR) Toxicol. Sci., April 1, 2006; 90(2): 269 - 295. [Abstract] [Full Text] [PDF]

				T Suzuki, S Hayashi, Y Miki, Y Nakamura, T Moriya, A Sugawara, T Ishida, N Ohuchi, and H Sasano Peroxisome proliferator-activated receptor {gamma} in human breast carcinoma: a modulator of estrogenic actions. Endocr. Relat. Cancer, March 1, 2006; 13(1): 233 - 250. [Abstract] [Full Text] [PDF]

				S. Han and J. Roman Rosiglitazone suppresses human lung carcinoma cell growth through PPAR{gamma}-dependent and PPAR{gamma}-independent signal pathways. Mol. Cancer Ther., February 1, 2006; 5(2): 430 - 437. [Abstract] [Full Text] [PDF]

				S. Han, J. D. Ritzenthaler, B. Wingerd, and J. Roman Activation of Peroxisome Proliferator-activated Receptor {beta}/{delta} (PPAR{beta}/{delta}) Increases the Expression of Prostaglandin E2 Receptor Subtype EP4: THE ROLES OF PHOSPHATIDYLINOSITOL 3-KINASE AND CCAAT/ENHANCER-BINDING PROTEIN {beta} J. Biol. Chem., September 30, 2005; 280(39): 33240 - 33249. [Abstract] [Full Text] [PDF]

				A. K. Khanna, M. Plummer, V. Nilakantan, and G. M. Pieper Recombinant p21 Protein Inhibits Lymphocyte Proliferation and Transcription Factors J. Immunol., June 15, 2005; 174(12): 7610 - 7617. [Abstract] [Full Text] [PDF]

				S. Han, H. N. Rivera, and J. Roman Peroxisome Proliferator-Activated Receptor-{gamma} Ligands Inhibit {alpha}5 Integrin Gene Transcription in Non-Small Cell Lung Carcinoma Cells Am. J. Respir. Cell Mol. Biol., April 1, 2005; 32(4): 350 - 359. [Abstract] [Full Text] [PDF]