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Rosiglitazone Suppresses Human Lung Carcinoma Cell Growth Through PPAR;-Dependent and PPAR;-Independent Signal Pathways

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Rosiglitazone Suppresses Human Lung Carcinoma Cell Growth Through PPAR;-Dependent and PPAR;-Independent Signal Pathways 430 Rosiglitazone suppresses human lung carcinoma cell growth through PPAR;-dependent and PPAR;-independent signal pathways ShouWei Han1 and Jesse Roman1,2 cascades, inhibits NSCLC cell proliferation through PPAR;-dependent and PPAR;-independent signals. [Mol 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Cancer Ther 2006;5(2):430–7] Department of Medicine, Emory University School of Medicine and 2Atlanta Veterans Affairs Medical Center, Atlanta, Georgia Introduction Peroxisome proliferator-activated receptors (PPAR; iso- Abstract types a, h/y, and g) are ligand-inducible nuclear trans- ; ; Peroxisome proliferator-activated receptors (PPAR ) cription factors (1). PPARs heterodimerize with retinoid X exert diverse effects on cancer cells. Recent studies receptors (2) and bind to PPAR response elements located ; showed that rosiglitazone, a synthetic ligand for PPAR , in the promoter region of PPAR target genes. These lipid- inhibits cell growth. However, the exact mechanisms sensitive receptors can be activated in a variable isotype- underlying this effect are still being explored, and the specific manner by natural fatty acids, leukotrienes, relevance of these findings to lung cancer remains prostaglandins, and some synthetic agonists, including unclear. Here, we report that rosiglitazone reduced the antidiabetic drugs, such as rosiglitazone, ciglitazone, and phosphorylation of Akt and increased phosphatase and pioglitazone. These drugs are also effective in regulating tensin homologue (PTEN) protein expression in non– cell activation, differentiation, proliferation, and/or apo- small cell lung carcinoma (NSCLC) cells (H1792 and ptosis (3, 4). H1838), and this was associated with inhibition of TheroleofPPARg, one PPAR isotype, has been NSCLC cell proliferation. These effects were blocked or extensively studied during the past several years. Synthetic ; diminished by GW9662, a specific PPAR antagonist. PPARg agonists specifically bind to PPARg isoforms, and ; However, transfection with a CMX-PPAR 2 overexpres- induce its activity, which in turn, results in altered sion vector restored the effects of rosiglitazone on Akt, expression of PPARg target genes. The efficacy of these PTEN, and cell growth in the presence of GW9662. In compounds as anticancer agents has been examined in a addition, rosiglitazone increased the phosphorylation of variety of cancers, including colon, breast, and prostate (5). A A AMP-activated protein kinase (AMPK ), a down- PPARg expression has also been shown in non–small cell stream kinase target for LKB1, whereas it decreased lung carcinoma (NSCLC) cells and was correlated with phosphorylation of p70 ribosomal protein S6 kinase tumor histologic type and grade (6). Activation of PPARg (p70S6K), a downstream target of mammalian target by troglitazone, ciglitazone, and pioglitazone caused of rapamycin (mTOR). Of note, GW9662 did not affect growth inhibition and apoptosis of NSCLC cells (7, 8). A the phosphorylation of AMPK and p70S6K protein. The Recently, studies in animal models of tumorigenesis inhibitory effect of rosiglitazone on NSCLC cell growth showed that treatment of A549 tumor-bearing severe was enhanced by the mTOR inhibitor rapamycin; combined immunodeficient mice with troglitazone or A however, it was blocked, in part, by the AMPK small pioglitazone inhibited primary tumor growth by 66.7% interfering RNA. Taken together, these findings show and significantly inhibited the number of spontaneous lung that rosiglitazone, via up-regulation of the PTEN/AMPK metastatic lesions. These observations suggest that PPARg and down-regulation of the Akt/mTOR/p70S6K signal ligands may serve as potential therapeutic agents in the management of NSCLC (9). Thus far, the mechanisms by which PPARg ligands suppress NSCLC cell growth have not been fully elucidat- Received 8/29/05; revised 11/9/05; accepted 12/8/05. ed. Here, we explore the effects of the PPARg ligand Grant support: American Lung Association Research grant RG-10215N (S.W. Han) and Department of Veterans Affairs Merit Review Grant rosiglitazone on NSCLC proliferation, and how its effects (J. Roman). might relate to the activation of the phosphatidylinositol 3- The costs of publication of this article were defrayed in part by the kinase (PI3K)/Akt and the AMP-activated protein kinase payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to (AMPK)/mammalian target of rapamycin (mTOR)/p70 indicate this fact. ribosomal S6 kinase (p70S6K) pathways. PI3K is a hetero- Requests for reprints: ShouWei Han, Division of Pulmonary, Allergy, dimeric enzyme involved in the regulation of mitogenesis, and Critical Care Medicine, Emory University School of Medicine, apoptosis, cell adhesion, and motility (10). This enzyme has Whitehead Bioresearch Building, 615 Michael Street, Suite 205-M, Atlanta, GA 30322. Phone: 404-712-2661; Fax: 404-712-2151. been suggested as a proto-oncogene in human cancer. E-mail: [email protected] mTOR has been shown to be a key kinase acting Copyright C 2006 American Association for Cancer Research. downstream of the activation of the PI3K, through which doi:10.1158/1535-7163.MCT-05-0347 it regulates an array of cellular processes. Signaling via MolCancerTher2006;5(2).February2006 Downloaded from mct.aacrjournals.org on October 2, 2021. © 2006 American Association for Cancer Research. Molecular Cancer Therapeutics 431 mTOR controls cell size and growth as well as other 1 ACi/mL [methyl-3H]thymidine (Amersham, Arlington functions, and this pathway represents a potential thera- Heights, IL; specific activity = 250 Ci/mmol) for an peutic target in graft rejection, certain cancers, and additional 24 hours. Afterwards, the cells were processed disorders characterized by inappropriate cell or tissue for Western blot analysis and the [methyl-3H]thymidine growth (11). mTOR signaling induced by hormones or incorporation assay as described below. growth factors and amino acids regulates the phosphory- Western Blot Analysis lation of several proteins, including p70S6K and eIF-4E The procedure was done as previously described (22). binding protein (4E-BP1), which are key regulators of Briefly, protein concentrations were determined by the translation, and are among the most well characterized Bio-Rad protein assay. Equal amounts of protein from targets of mTOR (12). This pathway is down-regulated by whole-cell lysates were solubilized in 2Â SDS-sample buffer AMPK and the tumor suppressor LKB1 (13–18), which is and separated on SDS/8% polyacrylamide gels. Blots were an upstream signal of mTOR. AMPK is the central incubated with antibodies raised against AMPKa and component of a protein kinase cascade that plays a key phosphorylated AMPKa, p70S6K and phosphorylated role in the regulation of energy control. Several findings p70S6K, Akt and its activated form, and PTEN (1:1,000). point to a link between AMPK and the growth and/or The blots were washed and followed by incubation with survival of some cancer cells (14, 15). It has been shown that a secondary goat antibody raised against rabbit IgG the tumor suppressor LKB1 is a kinase that has a major role conjugated to horseradish peroxidase (1:2,000; Cell Signal- in phosphorylating and activating AMPK (13). In addition, ing). The blots were washed, transferred to freshly made other studies indicate that mammalian homologue of enhanced chemiluminescence solution (Amersham) for 1 mTOR, which has been implicated in the pathogenesis of minute, and exposed to X-ray film. In controls, the anti- insulin resistance and many types of cancer, is inhibited by bodies were omitted or replaced with a control rabbit IgG. AMPK (14). Treatment with AMPK Small Interfering RNA We found that rosiglitazone inhibited the Akt/mTOR/ The AMPKa small interfering RNA (siRNA, ID no. 772) p70S6K pathway and stimulated phosphatase and tensin was purchased from Ambion (Austin, TX). Nonspecific homologue (PTEN) and AMPK signals in NSCLC cells control siRNA was purchased from Santa Cruz Biotech- through PPARg-dependent and PPARg-independent path- nology, Inc. (Santa Cruz, CA). For the transfection ways. These events were responsible for the growth- procedure, cells were grown to 50% confluence, and inhibitory effects of rosiglitazone. AMPKa or control siRNAs were transfected using the LipofectAMINE 2000 reagent (Invitrogen, Carlsbad, CA) Materials and Methods according to the manufacturer’s instructions. Briefly, Culture and Chemicals oligofectamine reagent was incubated with serum-free The human NSCLC cell lines H1838 and H1792 were medium for 10 minutes. Subsequently, a mixture of siRNA obtained from the American Type Culture Collection was added. After incubation for 15 minutes at room (Manassas, VA) and grown in RPMI 1640 supplemented temperature, the mixture was diluted with medium and with 10% heat-inactivated fetal bovine serum, HEPES buffer, added to each well. The final concentration of siRNA in 50 IU/mL penicillin/streptomycin, and 1 Ag amphotericin each well was 100 nmol/L. After culturing for 48 hours, (complete medium) as previously described (19). Rapamy- cells were washed and resuspended in new culture media cin and polyclonal antibodies specific for PTEN, AMPKa, in the presence or absence of rosiglitazone for up to 48 p70S6K, Akt, and their respective phosphorylated active hours for Western blot and cell growth assays. forms were purchased from Cell Signaling (Beverly, MA). [Methyl-3H]Thymidine Incorporation Assay GW9662,
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