Table of Contents Author Guidelines Submit a Manuscript
PPAR Research
Volume 2016 (2016), Article ID 8972570, 7 pages
http://dx.doi.org/10.1155/2016/8972570
Review Article

PPARγ as a Novel Therapeutic Target in Lung Cancer

1Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
2Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA

Received 18 June 2016; Accepted 7 August 2016

Academic Editor: George G. Chen

Copyright © 2016 Aravind T. Reddy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2016,” CA: A Cancer Journal for Clinicians, vol. 66, no. 1, pp. 7–30, 2016. View at Publisher · View at Google Scholar · View at Scopus
  2. G. P. Kalemkerian, W. Akerley, P. Bogner et al., “Small cell lung cancer,” Journal of the National Comprehensive Cancer Network, vol. 11, no. 1, pp. 78–98, 2013. View at Google Scholar
  3. Y. Sekido, K. M. Fong, and J. D. Minna, “Progress in understanding the molecular pathogenesis of human lung cancer,” Biochimica et Biophysica Acta (BBA)—Reviews on Cancer, vol. 1378, no. 1, pp. F21–F59, 1998. View at Publisher · View at Google Scholar · View at Scopus
  4. D. S. Ettinger, D. E. Wood, W. Akerley et al., “NCCN guidelines insights: non-small cell lung cancer, version 4.2016,” Journal of the National Comprehensive Cancer Network, vol. 14, no. 3, pp. 255–264, 2016. View at Google Scholar
  5. H. P. Koeffler, “Peroxisome proliferator-activated receptor gamma and cancers,” Clinical Cancer Research, vol. 9, no. 1, pp. 1–9, 2003. View at Google Scholar · View at Scopus
  6. M. Schapira, B. M. Raaka, H. H. Samuels, and R. Abagyan, “Rational discovery of novel nuclear hormone receptor antagonists,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 3, pp. 1008–1013, 2000. View at Publisher · View at Google Scholar · View at Scopus
  7. H. Gronemeyer, J.-Å. Gustafsson, and V. Laudet, “Principles for modulation of the nuclear receptor superfamily,” Nature Reviews Drug Discovery, vol. 3, no. 11, pp. 950–964, 2004. View at Publisher · View at Google Scholar · View at Scopus
  8. P. E. Almeida, A. B. Carneiro, A. R. Silva, and P. T. Bozza, “PPARγ expression and function in mycobacterial infection: roles in lipid metabolism, immunity, and bacterial killing,” PPAR Research, vol. 2012, Article ID 383829, 7 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  9. R. B. Clark, “The role of PPARs in inflammation and immunity,” Journal of Leukocyte Biology, vol. 71, no. 3, pp. 388–400, 2002. View at Google Scholar · View at Scopus
  10. 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. View at Publisher · View at Google Scholar · View at Scopus
  11. L. Michalik, B. Desvergne, and W. Wahli, “Peroxisome-proliferator-activated receptors and cancers: complex stories,” Nature Reviews Cancer, vol. 4, no. 1, pp. 61–70, 2004. View at Publisher · View at Google Scholar · View at Scopus
  12. L. Michalik and W. Wahli, “PPARs mediate lipid signaling in inflammation and cancer,” PPAR Research, vol. 2008, Article ID 134059, 15 pages, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. B. P. Kota, T. H.-W. Huang, and B. D. Roufogalis, “An overview on biological mechanisms of PPARs,” Pharmacological Research, vol. 51, no. 2, pp. 85–94, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. K. Tachibana, D. Yamasaki, K. Ishimoto, and T. Doi, “The role of PPARs in cancer,” PPAR Research, vol. 2008, Article ID 102737, 15 pages, 2008. View at Publisher · View at Google Scholar · View at Scopus
  15. A. K. Reka, M. T. Goswami, R. Krishnapuram, T. J. Standiford, and V. G. Keshamouni, “Molecular cross-regulation between PPAR-γ and other signaling pathways: implications for lung cancer therapy,” Lung Cancer, vol. 72, no. 2, pp. 154–159, 2011. View at Publisher · View at Google Scholar · View at Scopus
  16. M. Y. Li, T. W. Lee, A. P. Yim, and G. G. Chen, “Function of PPARgamma and its ligands in lung cancer,” Critical Reviews in Clinical Laboratory Sciences, vol. 43, no. 2, pp. 183–202, 2006. View at Google Scholar
  17. V. G. Keshamouni, S. Han, and J. Roman, “Peroxisome proliferator-activated receptors in lung cancer,” PPAR Research, vol. 2007, Article ID 90289, 10 pages, 2007. View at Publisher · View at Google Scholar · View at Scopus
  18. J. Berger and D. E. Moller, “The mechanisms of action of PPARs,” Annual Review of Medicine, vol. 53, pp. 409–435, 2002. View at Publisher · View at Google Scholar
  19. L. Fajas, D. Auboeuf, E. Raspé et al., “The organization, promoter analysis, and expression of the human PPARγ gene,” The Journal of Biological Chemistry, vol. 272, no. 30, pp. 18779–18789, 1997. View at Publisher · View at Google Scholar · View at Scopus
  20. L. Fajas, J.-C. Fruchart, and J. Auwerx, “PPARγ3 mRNA: a distinct PPARγ mRNA subtype transcribed from an independent promoter,” FEBS Letters, vol. 438, no. 1-2, pp. 55–60, 1998. View at Publisher · View at Google Scholar · View at Scopus
  21. V. G. Keshamouni, R. C. Reddy, D. A. Arenberg et al., “Peroxisome proliferator-activated receptor-γ activation inhibits tumor progression in non-small-cell lung cancer,” Oncogene, vol. 23, no. 1, pp. 100–108, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. 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-γ by troglitazone (TGZ) inhibits human lung cell growth,” Journal of Cellular Biochemistry, vol. 96, no. 4, pp. 760–774, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. Y. Tsubouchi, H. Sano, Y. Kawahito et al., “Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-γ agonists through induction of apoptosis,” Biochemical and Biophysical Research Communications, vol. 270, no. 2, pp. 400–405, 2000. View at Publisher · View at Google Scholar · View at Scopus
  24. K.-I. Inoue, Y. Kawahito, Y. Tsubouchi et al., “Expression of peroxisome proliferator-activated receptor (PPAR)-gamma in human lung cancer,” Anticancer Research, vol. 21, no. 4, pp. 2471–2476, 2001. View at Google Scholar · View at Scopus
  25. T.-H. Chang and E. Szabo, “Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor γ in non-small cell lung cancer,” Cancer Research, vol. 60, no. 4, pp. 1129–1138, 2000. View at Google Scholar · View at Scopus
  26. T. W. Lee, G. G. Chen, H. Xu et al., “Differential expression of inducible nitric oxide synthase and peroxisome proliferator-activated receptor gamma in non-small cell lung carcinoma,” European Journal of Cancer, vol. 39, no. 9, pp. 1296–1301, 2003. View at Publisher · View at Google Scholar · View at Scopus
  27. P. Sarraf, E. Mueller, W. M. Smith et al., “Loss-of-function mutations in PPARγ associated with human colon cancer,” Molecular Cell, vol. 3, no. 6, pp. 799–804, 1999. View at Publisher · View at Google Scholar · View at Scopus
  28. C. Giaginis, E. Politi, P. Alexandrou, J. Sfiniadakis, G. Kouraklis, and S. Theocharis, “Expression of peroxisome proliferator activated receptor-gamma (PPAR-γ) in human non-small cell lung carcinoma: correlation with clinicopathological parameters, proliferation and apoptosis related molecules and patients' survival,” Pathology and Oncology Research, vol. 18, no. 4, pp. 875–883, 2012. View at Publisher · View at Google Scholar · View at Scopus
  29. Y. Li, J. Zhang, F. J. Schopfer et al., “Molecular recognition of nitrated fatty acids by PPARγ,” Nature Structural & Molecular Biology, vol. 15, no. 8, pp. 865–867, 2008. View at Publisher · View at Google Scholar · View at Scopus
  30. A. T. Reddy, S. P. Lakshmi, Y. Zhang, and R. C. Reddy, “Nitrated fatty acids reverse pulmonary fibrosis by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages,” The FASEB Journal, vol. 28, no. 12, pp. 5299–5310, 2014. View at Publisher · View at Google Scholar · View at Scopus
  31. F. R. Balkwill, M. Capasso, and T. Hagemann, “The tumor microenvironment at a glance,” Journal of Cell Science, vol. 125, part 23, pp. 5591–5596, 2012. View at Publisher · View at Google Scholar · View at Scopus
  32. M. Li, T. W. Lee, A. P. C. Yim, T. S. K. Mok, and G. G. Chen, “Apoptosis induced by troglitazone is both peroxisome proliferator-activated receptor-γ- and ERK-dependent in human non-small lung cancer cells,” Journal of Cellular Physiology, vol. 209, no. 2, pp. 428–438, 2006. View at Publisher · View at Google Scholar
  33. Y. Bren-Mattison, V. Van Putten, D. Chan, R. Winn, M. W. Geraci, and R. A. Nemenoff, “Peroxisome proliferator-activated receptor-γ (PPARγ) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC),” Oncogene, vol. 24, no. 8, pp. 1412–1422, 2005. View at Publisher · View at Google Scholar · View at Scopus
  34. T. Satoh, M. Toyoda, H. Hoshino et al., “Activation of peroxisome proliferator-activated receptor-γ 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. View at Publisher · View at Google Scholar · View at Scopus
  35. S. Han, N. Sidell, P. B. Fisher, and J. Roman, “Up-regulation of p21 gene expression by peroxisome proliferator-activated receptor γ in human lung carcinoma cells,” Clinical Cancer Research, vol. 10, no. 6, pp. 1911–1919, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. S. Han and J. Roman, “Rosiglitazone suppresses human lung carcinoma cell growth through PPARγ-dependent and PPARγ-independent signal pathways,” Molecular Cancer Therapeutics, vol. 5, no. 2, pp. 430–437, 2006. View at Publisher · View at Google Scholar · View at Scopus
  37. S. Y. Lee, G. Y. Hur, K. H. Jung et al., “PPAR-γ agonist increase gefitinib's antitumor activity through PTEN expression,” Lung Cancer, vol. 51, no. 3, pp. 297–301, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. M. Wick, G. Hurteau, C. Dessev et al., “Peroxisome proliferator-activated receptor-γ is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth,” Molecular Pharmacology, vol. 62, no. 5, pp. 1207–1214, 2002. View at Publisher · View at Google Scholar · View at Scopus
  39. C. M. Lyon, D. M. Klinge, K. C. Do et al., “Rosiglitazone prevents the progression of preinvasive lung cancer in a murine model,” Carcinogenesis, vol. 30, no. 12, pp. 2095–2099, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. Y. Wang, M. James, W. Wen et al., “Chemopreventive effects of pioglitazone on chemically induced lung carcinogenesis in mice,” Molecular Cancer Therapeutics, vol. 9, no. 11, pp. 3074–3082, 2010. View at Publisher · View at Google Scholar · View at Scopus
  41. M.-Y. Li, A. W. Y. Kong, H. Yuan et al., “Pioglitazone prevents smoking carcinogen-induced lung tumor development in mice,” Current Cancer Drug Targets, vol. 12, no. 6, pp. 597–606, 2012. View at Publisher · View at Google Scholar · View at Scopus
  42. G. Bergers and L. E. Benjamin, “Tumorigenesis and the angiogenic switch,” Nature Reviews Cancer, vol. 3, no. 6, pp. 401–410, 2003. View at Publisher · View at Google Scholar · View at Scopus
  43. W. Guo and F. G. Giancotti, “Integrin signalling during tumour progression,” Nature Reviews Molecular Cell Biology, vol. 5, no. 10, pp. 816–826, 2004. View at Publisher · View at Google Scholar · View at Scopus
  44. R. M. Strieter, P. J. Polverini, S. L. Kunkel et al., “The functional role of the ELR motif in CXC chemokine-mediated angiogenesis,” The Journal of Biological Chemistry, vol. 270, no. 45, pp. 27348–27357, 1995. View at Publisher · View at Google Scholar · View at Scopus
  45. D. Panigrahy, S. Singer, L. Q. Shen et al., “PPARγ ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis,” The Journal of Clinical Investigation, vol. 110, no. 7, pp. 923–932, 2002. View at Publisher · View at Google Scholar · View at Scopus
  46. V. G. Keshamouni, D. A. Arenberg, R. C. Reddy, M. J. Newstead, S. Anthwal, and T. J. Standiford, “PPAR-γ activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer,” Neoplasia, vol. 7, no. 3, pp. 294–301, 2005. View at Publisher · View at Google Scholar · View at Scopus
  47. D. Bishop-Bailey and T. Hla, “Endothelial cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-Δ12,14-prostaglandin J2,” The Journal of Biological Chemistry, vol. 274, no. 24, pp. 17042–17048, 1999. View at Publisher · View at Google Scholar · View at Scopus
  48. M. Shimoda, K. T. Mellody, and A. Orimo, “Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression,” Seminars in Cell & Developmental Biology, vol. 21, no. 1, pp. 19–25, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. H. A. Burgess, L. E. Daugherty, T. H. Thatcher et al., “PPARγ agonists inhibit TGF-β induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 288, no. 6, pp. L1146–L1153, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. J. E. Milam, V. G. Keshamouni, S. H. Phan et al., “PPAR-γ agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 294, no. 5, pp. L891–L901, 2008. View at Publisher · View at Google Scholar · View at Scopus
  51. A. Maeda, S. Horikoshi, T. Gohda, T. Tsuge, K. Maeda, and Y. Tomino, “Pioglitazone attenuates TGF-beta(1)-induction of fibronectin synthesis and its splicing variant in human mesangial cells via activation of peroxisome proliferator-activated receptor (PPAR)gamma,” Cell Biology International, vol. 29, no. 6, pp. 422–428, 2005. View at Google Scholar
  52. S. Han, J. D. Ritzenthaler, H. N. Rivera, and J. Roman, “Peroxisome proliferator-activated receptor-γ ligands suppress fibronectin gene expression in human lung carcinoma cells: involvement of both CRE and Sp1,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 289, no. 3, pp. L419–L428, 2005. View at Publisher · View at Google Scholar · View at Scopus
  53. M. Fang, J. Yuan, C. Peng, and Y. Li, “Collagen as a double-edged sword in tumor progression,” Tumor Biology, vol. 35, no. 4, pp. 2871–2882, 2014. View at Publisher · View at Google Scholar · View at Scopus
  54. D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011. View at Publisher · View at Google Scholar · View at Scopus
  55. H. Paz, N. Pathak, and J. Yang, “Invading one step at a time: the role of invadopodia in tumor metastasis,” Oncogene, vol. 33, no. 33, pp. 4193–4202, 2014. View at Publisher · View at Google Scholar · View at Scopus
  56. H.-S. Jeon and J. Jen, “TGF-β signaling and the role of inhibitory smads in non-small cell lung cancer,” Journal of Thoracic Oncology, vol. 5, no. 4, pp. 417–419, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. V. G. Keshamouni, G. Michailidis, C. S. Grasso et al., “Differential protein expression profiling by iTRAQ-2DLC-MS/MS of lung cancer cells undergoing epithelial-mesenchymal transition reveals a migratory/invasive phenotype,” Journal of Proteome Research, vol. 5, no. 5, pp. 1143–1154, 2006. View at Publisher · View at Google Scholar · View at Scopus
  58. A. K. Reka, H. Kurapati, V. R. Narala et al., “Peroxisome proliferator-activated receptor-γ activation inhibits tumor metastasis by antagonizing smad3-mediated epithelial-mesenchymal transition,” Molecular Cancer Therapeutics, vol. 9, no. 12, pp. 3221–3232, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. R. Govindarajan, L. Ratnasinghe, D. L. Simmons et al., “Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes,” Journal of Clinical Oncology, vol. 25, no. 12, pp. 1476–1481, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. G. D. Girnun, E. Naseri, S. B. Vafai et al., “Synergy between PPARγ ligands and platinum-based drugs in cancer,” Cancer Cell, vol. 11, no. 5, pp. 395–406, 2007. View at Publisher · View at Google Scholar · View at Scopus
  61. R. C. Reddy, A. Srirangam, K. Reddy et al., “Chemotherapeutic drugs induce PPAR-γ expression and show sequence-specific synergy with PPAR-γ ligands in inhibition of non-small cell lung cancer,” Neoplasia, vol. 10, no. 6, pp. 597–603, 2008. View at Publisher · View at Google Scholar · View at Scopus
  62. T. A. Baudino, “Targeted cancer therapy: the next generation of cancer treatment,” Current Drug Discovery Technologies, vol. 12, no. 1, pp. 3–20, 2015. View at Publisher · View at Google Scholar · View at Scopus
  63. C.-J. Yao, G.-M. Lai, C.-F. Chan, A.-L. Cheng, Y.-Y. Yang, and S.-E. Chuang, “Dramatic synergistic anticancer effect of clinically achievable doses of lovastatin and troglitazone,” International Journal of Cancer, vol. 118, no. 3, pp. 773–779, 2006. View at Publisher · View at Google Scholar · View at Scopus