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[Cancer Research 60, 1129-1138, February 15, 2000]
© 2000 American Association for Cancer Research

Tumor Biology

Induction of Differentiation and Apoptosis by Ligands of Peroxisome Proliferator-activated Receptor {gamma} in Non-Small Cell Lung Cancer

Tsg-Hui Chang and Eva Szabo1

Cell and Cancer Biology Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Rockville, Maryland 20850

The peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) is a ligand-activated transcription factor belonging to the steroid receptor superfamily. It is a key regulator of adipogenic differentiation, the ligands of which have also been demonstrated to induce differentiation in human breast and colon cancer cell lines. This study examined PPAR{gamma} in non-small cell lung cancer (NSCLC). PPAR{gamma} mRNA and protein were expressed in NSCLC cell lines, with highest levels in adenocarcinomas. PPAR{gamma} protein was also expressed in 50% of primary lung cancers by immunohistochemistry. Treatment of multiple cell lines with two distinct PPAR{gamma} ligands in the presence of serum resulted in growth arrest, irreversible loss of capacity for anchorage-independent growth, decreased activity and expression of matrix metalloproteinase 2, and modulation of multiple markers in a manner consistent with differentiation. Specifically, there was up-regulation of general markers of the differentiated state such as gelsolin, Mad, and p21. Down-regulation of specific markers of progenitor lineages for the peripheral lung, i.e., the type II pneumocyte lineage markers MUC1 and surfactant protein-A and the Clara cell lineage marker CC10, also occurred. In addition, HTI56, a marker of terminally differentiated type I pneumocytes, was also induced. Consistent with a more mature, less malignant phenotype, ligand treatment also inhibited the expression of cyclin D1 and led to hypophosphorylation of the retinoblastoma protein. In contrast, in the absence of serum, ligand treatment rapidly resulted in apoptosis and substantially earlier onset of differentiation. Taken together, these results show that depending on the growth milieu, ligands of PPAR{gamma} induce differentiation and apoptosis in NSCLC, suggesting clinical utility for these agents.




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Nuclear Receptor Agonists As Potential Differentiation Therapy Agents for Human Osteosarcoma
Clin. Cancer Res., May 1, 2002; 8(5): 1288 - 1294.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
T. E. Akiyama, S. Sakai, G. Lambert, C. J. Nicol, K. Matsusue, S. Pimprale, Y.-H. Lee, M. Ricote, C. K. Glass, H. B. Brewer Jr., et al.
Conditional Disruption of the Peroxisome Proliferator-Activated Receptor {gamma} Gene in Mice Results in Lowered Expression of ABCA1, ABCG1, and apoE in Macrophages and Reduced Cholesterol Efflux
Mol. Cell. Biol., April 15, 2002; 22(8): 2607 - 2619.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
T.-H. Chang and E. Szabo
Enhanced Growth Inhibition by Combination Differentiation Therapy with Ligands of Peroxisome Proliferator-activated Receptor-{gamma} and Inhibitors of Histone Deacetylase in Adenocarcinoma of the Lung
Clin. Cancer Res., April 1, 2002; 8(4): 1206 - 1212.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
L. Kopelovich, J. R. Fay, R. I. Glazer, and J. A. Crowell
Peroxisome Proliferator-activated Receptor Modulators As Potential Chemopreventive Agents
Mol. Cancer Ther., March 1, 2002; 1(5): 357 - 363.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
D. J. A. Adamson, D. Frew, R. Tatoud, C. R. Wolf, and C. N. A. Palmer
Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor-gamma Signaling
Mol. Pharmacol., January 1, 2002; 61(1): 7 - 12.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
K. B. Kim, R. Lotan, P. Yue, M. B. Sporn, N. Suh, G. W. Gribble, T. Honda, G. S. Wu, W. K. Hong, and S.-Y. Sun
Identification of a Novel Synthetic Triterpenoid, Methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, That Potently Induces Caspase-mediated Apoptosis in Human Lung Cancer Cells
Mol. Cancer Ther., January 1, 2002; 1(3): 177 - 184.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
C. E. Clay, G.-i. Atsumi, K. P. High, and F. H. Chilton
Early de Novo Gene Expression Is Required for 15-Deoxy-Delta 12,14-prostaglandin J2-induced Apoptosis in Breast Cancer Cells
J. Biol. Chem., December 7, 2001; 276(50): 47131 - 47135.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
C. J. Hupfeld and R. H. Weiss
TZDs inhibit vascular smooth muscle cell growth independently of the cyclin kinase inhibitors p21 and p27
Am J Physiol Endocrinol Metab, August 1, 2001; 281(2): E207 - E216.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
A. C. C. Wang, X. Dai, B. Luu, and D. J. Conrad
Peroxisome Proliferator-Activated Receptor-gamma Regulates Airway Epithelial Cell Activation
Am. J. Respir. Cell Mol. Biol., June 1, 2001; 24(6): 688 - 693.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
S. W. Han, M. E. Greene, J. Pitts, R. K. Wada, and N. Sidell
Novel Expression and Function of Peroxisome Proliferator-activated Receptor Gamma (PPAR{{gamma}}) in Human Neuroblastoma Cells
Clin. Cancer Res., January 1, 2001; 7(1): 98 - 104.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
K. Subbaramaiah, D. T. Lin, J. C. Hart, and A. J. Dannenberg
Peroxisome Proliferator-activated Receptor gamma Ligands Suppress the Transcriptional Activation of Cyclooxygenase-2. EVIDENCE FOR INVOLVEMENT OF ACTIVATOR PROTEIN-1 AND CREB-BINDING PROTEIN/p300
J. Biol. Chem., April 6, 2001; 276(15): 12440 - 12448.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
R. A. Gupta, J. A. Brockman, P. Sarraf, T. M. Willson, and R. N. DuBois
Target Genes of Peroxisome Proliferator-activated Receptor gamma in Colorectal Cancer Cells
J. Biol. Chem., August 3, 2001; 276(32): 29681 - 29687.
[Abstract] [Full Text] [PDF]


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