PPARs in Lung Biology and DiseaseView this Special Issue
Research Article | Open Access
Rosiglitazone, an Agonist of PPAR, Inhibits Non-Small Cell Carcinoma Cell Proliferation In Part through Activation of Tumor Sclerosis Complex-2
PPAR ligands inhibit the proliferation of non-small cell lung carcinoma (NSCLC) cells in vitro. The mechanisms responsible for this effect remain incompletely elucidated, but PPAR ligands appear to inhibit the mammalian target of rapamycin (mTOR) pathway. We set out to test the hypothesis that PPAR ligands activate tuberous sclerosis complex-2 (TSC2), a tumor suppressor gene that inhibits mTOR signaling. We found that the PPAR ligand rosiglitazone stimulated the phosphorylation of TSC2 at serine-1254, but not threonine-1462. However, an antagonist of PPAR and PPAR siRNA did not inhibit these effects. Rosiglitazone also increased the phosphorylation of p38 MAPK, but inhibitors of p38 MAPK and its downstream signal MK2 had no effect on rosiglitazone-induced activation of TSC2. Activation of TSC2 resulted in downregulation of phosphorylated p70S6K, a downstream target of mTOR. A TSC2 siRNA induced p70S6K phosphorylation at baseline and inhibited p70S6K downregulation by rosiglitazone. When compared to a control siRNA in a thymidine incorporation assay, the TSC2 siRNA reduced the growth inhibitory effect of rosiglitazone by fifty percent. These observations suggest that rosiglitazone inhibits NSCLC growth partially through phosphorylation of TSC2 via PPAR-independent pathways.
- M. A. Socinski, “Combined modality trials in unresectable stage III non-small cell lung cancer: the cancer and leukemia group B experience,” Seminars in Oncology, vol. 32, 3, pp. S114–S118, 2005.
- C. A. Granville and P. A. Dennis, “An overview of lung cancer genomics and proteomics,” American Journal of Respiratory Cell and Molecular Biology, vol. 32, no. 3, pp. 169–176, 2005.
- S. A. Kliewer, K. Umesono, D. J. Noonan, R. A. Heyman, and R. M. Evans, “Convergence of 9-cis retinoic acid and peroxisome proliferator signaling pathways through heterodimer formation of their receptors,” Nature, vol. 358, no. 6389, pp. 771–774, 1992.
- S. Schmidt, E. Moric, M. Schmidt, M. Sastre, D. L. Feinstein, and M. T. Heneka, “Anti-inflammatory and antiproliferative actions of PPAR- agonists on T lymphocytes derived from MS patients,” Journal of Leukocyte Biology, vol. 75, no. 3, pp. 478–485, 2004.
- N. Hirase, T. Yanase, Y.-M. Mu et al., “Thiazolidinedione induces apoptosis and monocytic differentiation in the promyelocytic leukemia cell line HL60,” Oncology, vol. 57, 2, pp. 17–26, 1999.
- C. Grommes, G. E. Landreth, and M. T. Heneka, “Antineoplastic effects of peroxisome proliferatoractivated receptor agonists,” The Lancet Oncology, vol. 5, no. 7, pp. 419–429, 2004.
- S. Theocharis, H. Kanelli, E. Politi et al., “Expression of peroxisome proliferator activated receptor-gamma in non-small cell lung carcinoma: correlation with histological type and grade,” Lung Cancer, vol. 36, no. 3, pp. 249–255, 2002.
- T. Satoh, M. Toyoda, H. Hoshino et al., “Activation of peroxisome proliferator-activated receptor- stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells,” Oncogene, vol. 21, no. 14, pp. 2171–2180, 2002.
- S. Han, N. Sidell, P. B. Fisher, and J. Roman, “Up-regulation of p21 gene expression by peroxisome proliferator-activated receptor in human lung carcinoma cells,” Clinical Cancer Research, vol. 10, no. 6, pp. 1911–1919, 2004.
- V. G. Keshamouni, R. C. Reddy, D. A. Arenberg et al., “Peroxisome proliferator-activated receptor- activation inhibits tumor progression in non-small-cell lung cancer,” Oncogene, vol. 23, no. 1, pp. 100–108, 2004.
- S. Han and J. Roman, “Rosiglitazone suppresses human lung carcinoma cell growth through PPAR-dependent and PPAR-independent signal pathways,” Molecular Cancer Therapeutics, vol. 5, no. 2, pp. 430–437, 2006.
- X. Wang, A. Beugnet, M. Murakami, S. Yamanaka, and C. G. Proud, “Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins,” Molecular and Cellular Biology, vol. 25, no. 7, pp. 2558–2572, 2005.
- Y. Li, M. N. Corradetti, K. Inoki, and K.-L. Guan, “TSC2: filling the GAP in the mTOR signaling pathway,” Trends in Biochemical Sciences, vol. 29, no. 1, pp. 32–38, 2004.
- S. Han, N. Sidell, S. Roser-Page, and J. Roman, “Fibronectin stimulates human lung carcinoma cell growth by inducing cyclooxygenase-2 (COX-2) expression,” International Journal of Cancer, vol. 111, no. 3, pp. 322–331, 2004.
- S. Han, Z. M. Lei, and C. V. Rao, “Up-regulation of cyclooxygenase-2 gene expression by chorionic gonadotropin during the differentiation of human endometrial stromal cells into decidua,” Endocrinology, vol. 137, no. 5, pp. 1791–1797, 1996.
- J. J. Schlezinger, J. K. Emberley, and D. H. Sherr, “Activation of multiple mitogen-activated protein kinases in pro/pre-B cells by GW7845, a peroxisome proliferator-activated receptor agonist, and their contribution to GW7845-induced apoptosis,” Toxicological Sciences, vol. 92, no. 2, pp. 433–444, 2006.
- M. Li, T. W. Lee, T. S. K. Mok, T. D. Warner, A. P. C. Yim, and G. G. Chen, “Activation of peroxisome proliferator-activated receptor- by troglitazone (TGZ) inhibits human lung cell growth,” Journal of Cellular Biochemistry, vol. 96, no. 4, pp. 760–774, 2005.
- Y. Li, K. Inoki, P. Vacratsis, and K.-L. Guan, “The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14-3-3,” Journal of Biological Chemistry, vol. 278, no. 16, pp. 13663–13671, 2003.
- J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor (PPAR),” Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995.
- A. Galli, E. Ceni, D. W. Crabb et al., “Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPAR independent mechanisms,” Gut, vol. 53, no. 11, pp. 1688–1697, 2004.
- C.-W. Shiau, C.-C. Yang, S. K. Kulp et al., “Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPAR,” Cancer Research, vol. 65, no. 4, pp. 1561–1569, 2005.
- U. Valentiner, M. Carlsson, R. Erttmann, H. Hildebrandt, and U. Schumacher, “Ligands for the peroxisome proliferator-activated receptor- have inhibitory effects on growth of human neuroblastoma cells in vitro,” Toxicology, vol. 213, no. 1-2, pp. 157–168, 2005.
- P. Ferruzzi, E. Ceni, M. Tarocchi et al., “Thiazolidinediones inhibit growth and invasiveness of the human adrenocortical cancer cell line H295R,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 3, pp. 1332–1339, 2005.
- S.-I. Kawaguchi, K. Harada, Supriatno, H. Yoshida, and M. Sato, “Overexpression of tuberous sclerosis complex 2 exerts antitumor effect on oral cancer cell lines,” Oral Oncology, vol. 39, no. 8, pp. 836–841, 2003.
- A. Y. Choo, P. P. Roux, and J. Blenis, “Mind the GAP: Wnt steps onto the mTORC1 train,” Cell, vol. 126, no. 5, pp. 834–836, 2006.
- C. J. Potter, L. G. Pedraza, and T. Xu, “Akt regulates growth by directly phosphorylating Tsc2,” Nature Cell Biology, vol. 4, no. 9, pp. 658–665, 2002.
- K. Inoki, T. Zhu, and K.-L. Guan, “TSC2 mediates cellular energy response to control cell growth and survival,” Cell, vol. 115, no. 5, pp. 577–590, 2003.
- M. Nellist, M. A. Goedbloed, and D. J. J. Halley, “Regulation of tuberous sclerosis complex (TSC) function by 14-3-3 proteins,” Biochemical Society Transactions, vol. 31, no. 3, pp. 587–591, 2003.
- S. D. Shumway, Y. Li, and Y. Xiong, “14-3-3 binds to and negatively regulates the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product, tuberin,” Journal of Biological Chemistry, vol. 278, no. 4, pp. 2089–2092, 2003.
- S. Das, A. Tosaki, D. Bagchi, N. Maulik, and D. K. Das, “Potentiation of a survival signal in the ischemic heart by resveratrol through p38 mitogen-activated protein kinase/mitogen- and stress-activated protein kinase 1/cAMP response element-binding protein signaling,” Journal of Pharmacology and Experimental Therapeutics, vol. 317, no. 3, pp. 980–988, 2006.
- H. Ishida, K. Ohkawa, A. Hosui et al., “Involvement of p38 signaling pathway in interferon--mediated antiviral activity toward hepatitis C virus,” Biochemical and Biophysical Research Communications, vol. 321, no. 3, pp. 722–727, 2004.
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