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</svg> Ligands in Lung Cancer

Nemenoff, Raphael A.; Weiser-Evans, Mary; Winn, Robert A.

doi:https://doi.org/10.1155/2008/156875

PPAR Research

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Review Article | Open Access

Volume 2008 | Article ID 156875 | https://doi.org/10.1155/2008/156875

Activation and Molecular Targets of Peroxisome Proliferator-Activated Receptor- Ligands in Lung Cancer

Raphael A. Nemenoff,¹Mary Weiser-Evans,¹and Robert A. Winn²

Academic Editor: Dipak Panigrahy

Received10 Mar 2008

Accepted29 Apr 2008

Published26 May 2008

Abstract

Lung cancer is the leading cause of cancer death, and five-year survival remains poor, raising the urgency for new treatment strategies. Activation of PPAR represents a potential target for both the treatment and prevention of lung cancer. Numerous studies have examined the effect of thiazolidinediones such as rosiglitazone and pioglitazone on lung cancer cells in vitro and in xenograft models. These studies indicate that activation of PPAR inhibits cancer cell proliferation as well as invasiveness and metastasis. While activation of PPAR can occur by direct binding of pharmacological ligands to the molecule, emerging data indicate that PPAR activation can occur through engagement of other signal transduction pathways, including Wnt signaling and prostaglandin production. Data, both from preclinical models and retrospective clinical studies, indicate that activation of PPAR may represent an attractive chemopreventive strategy. This article reviews the existing biological and mechanistic experiments focusing on the role of PPAR in lung cancer, focusing specifically on nonsmall cell lung cancer.

1. Introduction

Lung cancer is the leading cause of cancer death for both men and women in the USA. In fact, more deaths will occur this year due to lung cancer than breast, prostate, and colorectal cancers combined [1]. In spite of intensive research, 5-year survival in patients with lung cancer remains dismally low, with overall survival at 15% [2]. A major reason for this problem is the presence of metastasis at the time of diagnosis. While smoking cessation will clearly reduce the risk of lung cancer, a majority of diagnosed cases are being detected in exsmokers [3]. Therefore, in addition to new chemotherapeutic approaches, there appears to be a critical need for chemopreventive strategies which can be administered to patients at risk for developing lung cancer. In this article, we will review recent data, both from basic sciences experiments and from clinical studies indicating that activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) may represent a novel strategy for the treatment and prevention of lung cancer.

2. Biology of Lung Cancer

Lung cancers are categorized as small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). As a group, the NSCLC constitute the bulk of lung cancers and are subdivided into squamous, adenocarcinoma, and large cell carcinoma phenotypes. Selective changes in specific oncogenes can be used to distinguish the two types of cancer. Activating mutations in ras are associated with NSCLC, with a mutation at codon 12 of the Ki-Ras gene observed in approximately 30% of adenocarcinomas, and just under 10% of other NSCLC types [4]. These mutations appear to be virtually absent from SCLC [5]. In mice, Ki-Ras mutations are found in over 90% of spontaneous and chemically induced lung tumors [6]. Overexpression of the c-myc gene is also frequently observed in NSCLC, but appears to be more prevalent in SCLC [7]. Elevated expression of the HER-2/neu gene, a member of the epidermal growth factor receptor family has also been observed in 35% of adenocarcinomas and a slightly lower percentage of squamous carcinomas [8]. Alterations in tumor suppressor genes have also been reported. Mutations in p53 have been detected in 90% of SCLC and 50% of NSCLC [7]. Mutations in the retinoblastoma gene are more specific for SCLC, occurring in more than 90%, while only a small fraction of NSCLC have mutations in this gene. Recently, mRNA expression profiling has been used to define subclasses of lung adenocarcinoma, which can be defined by distinct patterns of gene expression [9, 10]. These studies suggest that NSCLC may in fact represent multiple diseases characterized by distinct molecular pathways. In contrast to most NSCLC, SCLC displays neuroendocrine features exemplified by the presence of cytoplasmic neurosecretory granules containing a wide variety of mitogenic neuropeptides including gastrin-releasing peptide, arginine vasopressin, neurotensin, cholecystokinin, and many others [11, 12]. Significantly, SCLC also expresses G protein-coupled receptors (GPCR) for these neuropeptides, thereby establishing autocrine-stimulated cell growth. Therapeutic strategies have targeted these neuropeptides using inhibitors of GPCRs. However, the existence of potentially redundant loops mediated by multiple neuropeptides has limited the usefulness of this strategy.

Recently, a great deal of attention has been focused on the EGF receptor, and the use of selective inhibitors of the EGF receptor tyrosine kinase (EGFR-TKI). These agents (gefitinib and erlotinib) have shown therapeutic efficacy in a subset of NSCLC patients which have somatic mutations in this receptor [13, 14]. However, responses have also been observed in patients with wild-type EGFR. Identifying strategies which would sensitize patients to EGFR-TKI therapy is under active investigation (see [15] for review).

3. PPAR Activation

PPAR is a member of nuclear receptor superfamily. Two major isoforms have been described, PPAR1 and PPAR2 (see [16] for review). These are splice variants, with PPAR2 being expressed predominantly in adipose tissue, whereas PPAR1 has a more widespread distribution, and is expressed in cancer cells, including lung cancer [16]. More recently a number of additional splice variants have been identified [17]. The role of these forms of PPAR remains to be established. The structure of PPAR is similar to that of most nuclear receptors; the core of the molecule consists of a DNA-binding region (DBD) and a ligand-binding region (LBD), separated by a hinge region. There are two activation domains, AF-1 at the amino terminal and AF-2 at the carboxyl terminal. The classic pathway of PPAR activation involves binding as a heterodimer with the retinoic acid X receptor to specific DNA sequences (PPAR-RE). The consensus PPAR site consists of a direct repeat of the sequence AGGTCA, separated by a single nucleotide, designated a DR-1 site. Ligand binding to the LBD causes a conformational change, which results in the release of corepressors and the binding of coactivators, resulting in increased transcription of target genes.

PPAR is activated by polyunsaturated fatty acids and eicosanoids. In particular, 15-deoxy-- has been shown to specifically activate PPAR with micromolar affinity [18]. Lipoxygenase products of linoleic acid, 9- and 13-HODE have micromolar affinities for PPAR [19]. It is not clear whether any of these agents are actual physiologic regulators of PPAR, and a recent study has found that endogenous levels of do not change during adipocyte differentiation [20]. Synthetic activators of PPAR include the thiazolidinediones, such as rosiglitazone and pioglitazone [21]. These compounds have insulin-sensitizing and antidiabetic activity, which is likely mediated at least in part through PPAR activation. Finally, NSAIDs, which inhibit eicosanoid production, activate PPAR albeit at higher concentrations than required for COX inhibition [22]. While all of these agents can activate PPAR, it is clear that they also stimulate “off-target” pathways which may impact their therapeutic potency [23]. Finally, it should be noted that PPAR can directly bind to other transcription factors, including NF-κB and Sp1 [24]. This mechanism of action complicates the spectrum of genes that could be regulated by PPAR by engaging regulatory elements distinct from classic PPAR-RE sites [25].

4. Clinical Associations with PPAR in Lung Cancer

Analysis of human lung tumors has reported that decreased expression of PPAR is correlated with a poor prognosis [26]. Further work indicated that expression of PPAR as detected by immunohistochemistry was more frequently detected in well-differentiated adenocarcinomas, compared to poorly differentiated ones. Recently, a retrospective study demonstrated a 33% reduction in lung cancer risk in diabetic patients using the TZD rosiglitazone [27]. An even more dramatic reduction was observed in African-American patients (75%). This decreased risk appeared to be specific for lung cancer, and no protective effect was observed for prostate or colon cancer. Genetic variants in the PPAR gene have been identified which are associated with a decreased risk for lung cancer [28]. These findings suggest that chemoprevention strategies using PPAR activators may be an attractive approach in patients at risk for lung cancer, and that polymorphisms in the PPAR gene may be a way to screen those patients. There are several chemoprevention trials being initiated using TZDs. However, a concern in these studies is the association of higher rates of adverse cardiac events with chronic TZD treatment, especially with rosiglitazone [29]. As discussed below, agents which target PPAR through alternative pathways may therefore represent novel therapeutic targets.

5. Biological Effects of PPAR in Lung Cancer Cells

A number of studies have examined the effects of TZDs on the growth of lung cancer cells. The majority of these studies have focused on NSCLC. Administration of TZDs has been shown to inhibit growth and induce apoptosis in numerous NSCLC cell lines [30–34]. While the mechanisms for these effects are not completely understood, they appear to be mediated through both PPAR-dependent and independent effects. Induction of apoptosis may involve the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in some cancer cell lines [35]; these effects appear to be mediated through PPAR-independent pathways. Recent studies have also demonstrated that PPAR activation induces proline oxidase, which will result in increased production of cytotoxic reactive oxygen species (ROS) [36]. Growth arrest may be mediated through induction of the cyclin kinase inhibitor p21 [37]. In this case, the mechanism of action involves PPAR-dependent induction of p21 through interactions with other transcription factors. Several studies, including work from our own laboratory have demonstrated that activation of PPAR leads to promotion of a more highly differentiated phenotype in NSCLC [32, 38]. This can be assessed by growing cells in 3-dimensional tissue culture, which has been shown to reveal epithelial features. E-cadherin is perhaps to most widely studied marker of epithelial differentiation, and both pharmacological PPAR activators and molecular overexpression of PPAR had shown increased protein and mRNA for E-cadherin. Epithelial mesenchymal transition has been associated with cancer progression and metastasis [39]. While this is still somewhat of a controversial area [40], activation of PPAR in lung cancer cells appears to inhibit invasiveness, at least in part through inhibiting or reversing EMT.

It has become evident during the past several years, that while genetic changes in cancer cells are critical for tumor initiation, progression and metastasis entail a critical contribution from the tumor microenvironment [41]. Specifically, interactions of tumor cells with vascular cells, innate immune cells, and fibroblasts control tumor angiogenesis and promote a more aggressive phenotype. These cell-cell interactions are mediated through cytokines and growth factors initially produced by the tumor cells which recruit stromal cells. Among these cytokines are factors such as MCP-1 and CCL5, critical for macrophage recruitment, and VEGF and other proangiogenic cytokines such as IL-8 which recruit vascular cells [42]. Transcriptional control of these factors is mediated by multiple transcription factors, but specifically, it has been shown that two specific factors, NF-κB and HIF-1, are critical for many of these molecules. Several studies have demonstrated that PPAR activation can inhibit activation of NF-κB in NSCLC [43, 44]. While effects on HIF-1 have not been documented in lung cancer cells, PPAR has been shown to inhibit HIF-1 in other systems [45]. These data indicate that activation of PPAR may disrupt communication between cancer cells and the surrounding tumor microenvironment, thus blocking progression and metastasis, distinct from antiproliferative effects on the tumor cells. In lung cancer, where metastasis has often occurred at the time of diagnosis, agents, which specifically target tumor-stromal interactions, represent a novel therapeutic approach.

6. Upstream Activation of PPAR

While TZDs have received most of the attention as PPAR activators, it is becoming apparent that activation of PPAR can occur as a consequence of activation of other signaling pathways (see Figure 1). Phosphorylation by the ERK members of the MAP kinase family has been shown to decrease PPAR activity, likely through altering the affinity for ligand binding [46]. Work in endothelial cells has demonstrated that flow-mediated activation of ERK5, a member of the MAP kinase family, results in activation of PPAR [47], which may mediate anti-inflammatory effects associated with laminar flow. In this case, the mechanism of activation involves direct binding of ERK5 to the hinge region of PPAR. In lung cancer, our studies have focused on the role of the Wnt signaling pathway. While canonical Wnt signaling has been implicated as promoting colon carcinogenesis, the role of the Wnt pathway in nonsmall cell lung cancer appears to be more complex. Our studies have demonstrated that Wnt7a signaling through its receptor Fzd9 inhibits transformed growth of NSCLC cell lines [48]. Further studies indicated that this pathway leads to increased PPAR activity through activation of ERK5, and that this increase in PPAR activity mediated the antitumorigenic effects of Wnt7a/Fzd9 signaling [49].

Figure 1

Activation pathways for PPAR. PPAR forms a heterodimer with the retinoic acid X receptor (RXR). Activation can occur by thiazolidinidiones (TZD) such as rosiglitazone or pioglitazone directly binding to the ligand-binding domain. This results in the dissociation of corepressors such as NCor and SMRT, and the binding of coactivators such as p300 and Src, mediating activation of transcription. In lung cancer cells, binding of Wnt7a to its cognate receptor Fzd9 leads to activation of ERK5, which presumably directly binds to the hinge region of PPAR mediating activation. Prostacyclin (PGI) and analogs such as iloprost can also lead to PPAR activation, and this may involve ERK5 activation. Conversely, activation of the ERK or JNK family of MAP kinases can inhibit PPAR activation; this is mediated through direct phosphorylation of the molecule which alters the ligand binding affinity. Finally, activation of PPAR/RXR heterodimers may be activated through retinoic acid (RA) binding to RXR.

A connection has also been made between prostacyclin and activation of PPAR. Prostaglandin (, prostacyclin), produced through the cyclooxygenase pathway via prostacyclin synthase (PGIS), is a bioactive lipid with anti-inflammatory, antiproliferative, and potent antimetastatic properties [50, 51]. Our laboratory has shown that transgenic mice with selective pulmonary synthase (PGIS) overexpression exhibited significantly reduced lung tumor multiplicity and incidence in response to either chemical carcinogens or exposure to tobacco smoke [52, 53], suggesting that manipulation of the arachidonic acid pathway downstream from COX is a target for lung cancer prevention. IIoprost, a long-lasting prostacyclin analog, also inhibits lung tumorigenesis in wild-type mice. can signal through a specific cell surface receptor, designated IP, which is a member of the G-protein coupled receptor family, and signals through increases in cAMP [54]. However, has been shown to signal through activation of PPARs, with reports of both PPAR [55] and PPARδ activation [56, 57]. To define the downstream effector of in the chemoprevention of lung cancer, studies were performed in which mice overexpressing PGIS were crossed with mice deficient in IP (A. M. Meyer et al., unpublished observations). In a chemical carcinogenesis model, lack of IP did not affect protection against lung tumorigenesis mediated by PGIS overexpression, suggesting IP-independent pathways. Further study is required to whether prostacyclin can activate PPAR in vivo, and whether this effect is mediated through IP or represents a direct, IP-independent activation.

To test the role of PPAR in chemoprevention of lung cancer, we have developed transgenic mice overexpressing PPAR under the control of the surfactant protein C promoter, which targets expression to the distal lung epithelium. In a chemical carcinogenesis model, these mice showed a marked protection against developing lung tumors [44]. While the connection between prostacyclin analogs and PPAR activation needs to be more precisely defined, from a therapeutic standpoint, the ability to activate PPAR through non-TZD mechanisms represents an attractive strategy that may avoid some of the deleterious effects seen with TZD administration.

7. Mechanisms of PPAR Action in Lung Cancer Cells

In spite of intensive study examining the biological effects of PPAR activation in lung cancer, much less is know regarding the direct targets of PPAR (see Figure 2). As a member of the nuclear receptor superfamily, PPAR is a ligand-activated transcription factor. Thus, one assumes that there are direct transcriptional targets, where PPAR, in combination with the RXR receptor, binds to regulatory elements and induced transcription. These targets have been difficult to identify in cancer cells. In fact, most of the responses that have been demonstrated involve suppression of target genes (e.g., cytokines). While PPAR has been shown to upregulate E-cadherin in NSCLC, there are no studies demonstrating direct binding of PPAR to the E-cadherin promoter. A family of transcription factors have been identified which act as suppressors of E-cadherin expression. Members of this family include Snail1, Snail2 (Slug), ZEB1, and Twist [58, 59] are potent inducers of EMT. Both Snail and Twist appear to play critical roles in breast cancer metastasis [60, 61]. Overexpression of ZEB-1 has been implicated in mediating EMT in NSCLC cells [62].

Figure 2

Effector pathways for PPAR in NSCLC. PPAR can increase either expression of enzymatic activity of PTEN. This results in inhibition of Akt activation (pAkt), which may be involved in the growth inhibitory responses seen with PPAR activation. Decreased Akt activity also can lead to decreased activity of the transcription factor NF-κB. NF-κB is a critical transcription factor in the production of proangiogenic and proinflammatory cytokines such as VEGF, IL-8. Decreased production of these factors would be expected to inhibit recruitment of inflammatory cells such as macrophages, and block tumor angiogenesis. PPAR-mediated suppression of members of the Snail family of transcription factors, such as Snail, Zeb, or Twist, would lead to derepression of E-cadherin expression and promote the epithelial phenotype, leading to decreased migration and invasiveness. PPAR-mediated suppression of COX-2 expression in NSCLC has been shown by several investigators. This would result in decreased production, which will impact growth. TZDs can inhibit production through a PPAR-independent pathway involving induction of 15-hydroxyprostaglandin dehydrogenase (PGDH). Pathways indicated in green are increased or activated by PPAR, while those in red represent pathways that are inhibited or repressed.

Several studies have reported increased expression of the protein and lipid phosphatase PTEN in response to PPAR activation [63, 64]. Increased expression/activity of PTEN would be anticipated to inhibit signaling through PI-3 kinase/Akt, and downstream effectors such as mTOR. Decreased activation of Akt could lead to inhibition of NF-κB signaling [65–67], although the molecular mechanisms are not well defined.

Elevated expression of cyclooxygenase-2 (COX-2) is common in NSCLC, and mediates increased production of [68]. Activation of PPAR has been shown in inhibit COX-2 expression and decrease PGE₂ production in NSCLC [44, 69]. While the mechanisms whereby contributes to growth and progression of NSCLC are not completely understood, recent data in colon cancer have shown that acting through its cell surface receptor can engage -catenin signaling, leading to proliferation [70]. Consistent with such a model, TZDs also inhibit expression of the EP2 receptor, which couples to -catenin signaling [71]. Regulation of production by TZDs can also occur through PPAR-independent pathways. Both rosiglitazone and pioglitazone can directly activate 15 hydroxyprostaglandin dehydrogenase, promoting breakdown of .

8. Conclusions and Future Directions

Activation of PPAR appears to inhibit lung tumorigenesis at several different stages. Animal studies indicate that increased PPAR may be chemopreventive against developing lung tumors, suggesting that it can block the early stages of epithelial transformation. In established lung cancer, activation of PPAR can inhibit proliferation, induce apoptosis, and promote a less invasive phenotype through promoting epithelial differentiation, and perhaps blocking EMT. Finally, through disruption of tumor-stromal communication via inhibition of chemokine production, PPAR can negatively impact tumor progression and metastasis. These data make PPAR activators attractive agents for the treatment and prevention of lung cancer.

However, a number of significant issues remain to be resolved. In many of the studies described in this article, it is not clear if the biological responses are mediated through “on-target” activation of PPAR, or through other “off-target” effects. A strategy to address this issue is the use of molecular approaches, either overexpressing or silencing PPAR in cancer cells to complement studies with pharmacological agents. Genetic mouse models using targeted knockouts of PPAR in either cancer cells or stromal compartments will also be informative. This strategy also applies to defining the mechanisms mediating the adverse cardiovascular events reported in patients taking TZDs. Defining the molecular targets of TZDs mediating a specific response will be critical in the further development of second-generation PPAR drugs. If adverse cardiac events are mediated through “off-target” effects, then a more selective PPAR activator would be therapeutically effective, without leading to adverse cardiac events. Alternatively, if the antitumorigenic effects of TZDs are mediated through “off-target” effectors, then identifying these pathways would lead to novel therapeutic targets. Finally, the majority of studies have focused on NSCLC. Studies defining mechanisms of activation and downstream targets in SCLC are needed to determine if PPAR represents a therapeutic target for treating these forms of lung cancer.

Acknowledgment

This work was supported by National Institutes of Health Grants nos. CA103618, CA108610, and CA58187.

References

K. M. Kerr, “Pulmonary preinvasive neoplasia,” Journal of Clinical Pathology, vol. 54, no. 4, pp. 257–271, 2001.
View at: Publisher Site | Google Scholar
C. M. Michaud, C. J. L. Murray, and B. R. Bloom, “Burden of disease—implications for future research,” Journal of the American Medical Association, vol. 285, no. 5, pp. 535–539, 2001.
View at: Publisher Site | Google Scholar
A. Jemal, R. Siegel, E. Ward et al., “Cancer statistics, 2006,” Ca: A Cancer Journal for Clinicians, vol. 56, no. 2, pp. 106–130, 2006.
View at: Google Scholar
G. Giaccone, “Oncogenes and antioncogenes in lung tumorigenesis,” Chest, vol. 109, supplement 5, pp. 130S–134S, 1996.
View at: Publisher Site | Google Scholar
T. Mitsudomi, J. Viallet, J. L. Mulshine, R. I. Linnoila, J. D. Minna, and A. F. Gazdar, “Mutations of ras genes distinguish a subset of non-small-cell lung cancer cell lines from small-cell lung cancer cell lines,” Oncogene, vol. 6, no. 8, pp. 1353–1362, 1991.
View at: Google Scholar
A. M. Malkinson, “Molecular comparison of human and mouse pulmonary adenocarcinomas,” Experimental Lung Research, vol. 24, no. 4, pp. 541–555, 1998.
View at: Google Scholar
A. F. Gazdar and D. P. Carbone, The Biology and Molecular Genetics of Lung Cancer, Landes, Austin, Tex, USA, 1994.
D. B. Weiner, J. Nordberg, R. Robinson et al., “Expression of the neu gene-encoded protein (P185(neu)) in human non-small cell carcinomas of the lung,” Cancer Research, vol. 50, no. 2, pp. 421–425, 1990.
View at: Google Scholar
A. Bhattacharjee, W. G. Richards, J. Staunton et al., “Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 24, pp. 13790–13795, 2001.
View at: Publisher Site | Google Scholar
M. E. Garber, O. G. Troyanskaya, K. Schluens et al., “Diversity of gene expression in adenocarcinoma of the lung,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 24, pp. 13784–13789, 2001.
View at: Publisher Site | Google Scholar
P. A. Bunn Jr., D. Chan, D. G. Dienhart, R. Tolley, M. Tagawa, and P. B. Jewett, “Neuropeptide signal transduction in lung cancer: clinical implications of bradykinin sensitivity and overall heterogeneity,” Cancer Research, vol. 52, no. 1, pp. 24–31, 1992.
View at: Google Scholar
G. D. Sorenson, O. S. Pettengill, T. Brinck-Johnsen, C. C. Cate, and L. H. Maurer, “Hormone production by cultures of small-cell carcinoma of the lung,” Cancer, vol. 47, no. 6, pp. 1289–1296, 1981.
View at: Publisher Site | Google Scholar
T. J. Lynch, D. W. Bell, R. Sordella et al., “Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib,” The New England Journal of Medicine, vol. 350, no. 21, pp. 2129–2139, 2004.
View at: Publisher Site | Google Scholar
J. G. Paez, P. A. Jänne, J. C. Lee et al., “EGFR mutations in lung, cancer: correlation with clinical response to gefitinib therapy,” Science, vol. 304, no. 5676, pp. 1497–1500, 2004.
View at: Publisher Site | Google Scholar
D. A. Haber, D. W. Bell, R. Sordella et al., “Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 70, pp. 419–426, 2005.
View at: Publisher Site | Google Scholar
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 Site | Google Scholar
Y. Chen, A. R. Jimenez, and J. D. Medh, “Identification and regulation of novel PPAR- $γ$ splice variants in human THP-1 macrophages,” Biochimica et Biophysica Acta, vol. 1759, no. 1-2, pp. 32–43, 2006.
View at: Publisher Site | Google Scholar
S. A. Kliewer, J. M. Lenhard, T. M. Willson, I. Patel, D. C. Morris, and J. M. Lehmann, “A prostaglandin $J_{2}$ metabolite binds peroxisome proliferator-activated receptor $γ$ and promotes adipocyte differentiation,” Cell, vol. 83, no. 5, pp. 813–819, 1995.
View at: Publisher Site | Google Scholar
L. Nagy, P. Tontonoz, J. G. A. Alvarez, H. Chen, and R. M. Evans, “Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR $γ$ ,” Cell, vol. 93, no. 2, pp. 229–240, 1998.
View at: Publisher Site | Google Scholar
L.C. Bell-Parikh, T. Ide, J. A. Lawson, P. McNamara, M. Reilly, and G. A. FitzGerald, “Biosynthesis of 15-deoxy- $Δ^{12, 14}$ -PG $J_{2}$ and the ligation of PPAR $γ$ ,” Journal of Clinical Investigation, vol. 112, no. 6, pp. 945–955, 2003.
View at: Publisher Site | Google Scholar
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 $γ$ (PPAR $γ$ ),” Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995.
View at: Publisher Site | Google Scholar
J. M. Lehmann, J. M. Lenhard, B. B. Oliver, G. M. Ringold, and S. A. Kliewer, “Peroxisome proliferator-activated receptors $α$ and $γ$ are activated by indomethacin and other non-steroidal anti-inflammatory drugs,” Journal of Biological Chemistry, vol. 272, no. 6, pp. 3406–3410, 1997.
View at: Publisher Site | Google Scholar
R. A. Nemenoff, “Peroxisome proliferator-activated receptor- $γ$ in lung cancer: defining specific versus “off-target” effectors,” Journal of Thoracic Oncology, vol. 2, no. 11, pp. 989–992, 2007.
View at: Publisher Site | Google Scholar
F. Chen, M. Wang, J. P. O'Connor, M. He, T. Tripathi, and L. E. Harrison, “Phosphorylation of PPAR $γ$ via active ERK1/2 leads to its physical association with p65 and inhibition of NF- $κ$ $β$ ,” Journal of Cellular Biochemistry, vol. 90, no. 4, pp. 732–744, 2003.
View at: Publisher Site | Google Scholar
C. A. Argmann, T.-A. Cock, and J. Auwerx, “Peroxisome proliferator-activated receptor $γ$ : the more the merrier?” European Journal of Clinical Investigation, vol. 35, no. 2, pp. 82–92, 2005.
View at: Publisher Site | Google Scholar
H. Sasaki, M. Tanahashi, H. Yukiue et al., “Decreased perioxisome proliferator-activated receptor gamma gene expression was correlated with poor prognosis in patients with lung cancer,” Lung Cancer, vol. 36, no. 1, pp. 71–76, 2002.
View at: Publisher Site | Google Scholar
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 Site | Google Scholar
D. Chen, G. Jin, Y. Wang et al., “Genetic variants in peroxisome proliferator-activated receptor- $?$ gene are associated with risk of lung cancer in a Chinese population,” Carcinogenesis, vol. 29, no. 2, pp. 342–350, 2008.
View at: Publisher Site | Google Scholar
“Thiazolidinediones and cardiovascular disease,” The Medical Letter on Drugs and Therapeutics, vol. 49, no. 1265, pp. 57–58, 2007.
View at: Google Scholar
M. Li, T. W. Lee, A. P. C. Yim, T. S. K. Mok, and G. G. Chen, “Apoptosis induced by troglitazone is both peroxisome proliterator-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 Site | Google Scholar
S. Han and J. Roman, “Rosiglitazone suppresses human lung carcinoma cell growth through PPAR $γ$ -dependent and PPAR $γ$ -independent signal pathways,” Molecular Cancer Therapeutics, vol. 5, no. 2, pp. 430–437, 2006.
View at: Publisher Site | Google Scholar
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
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.
View at: Publisher Site | Google Scholar
M. Wick, G. Hurteau, C. Dessev et al., “Peroxisome proliferator-activated receptor- $?$ 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 Site | Google Scholar
W. Zou, X. Liu, P. Yue, F. R. Khuri, and S.-Y. Sun, “PPAR $γ$ ligands enhance TRAIL-induced apoptosis through DR5 upregulation and c-FLIP downregulation in human lung cancer cells,” Cancer Biology and Therapy, vol. 6, no. 1, pp. 99–106, 2007.
View at: Google Scholar
K. Y. Kim, J. H. Ahn, and H. G. Cheon, “Apoptotic action of peroxisome proliferator-activated receptor- $γ$ activation in human non-small-cell lung cancer is mediated via proline oxidase-induced reactive oxygen species formation,” Molecular Pharmacology, vol. 72, no. 3, pp. 674–685, 2007.
View at: Publisher Site | Google Scholar
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 Site | Google Scholar
Y. Bren-Mattison, V. Van Putten, D. Chan, R. Winn, M. W. Geraci, and R. A. Nemenoff, “Peroxisome proliferator-activated receptor- $γ$ (PPAR $γ$ ) 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 Site | Google Scholar
C. Scheel, T. Onder, A. Karnoub, R. A. Weinberg, and J. E. Talmadge, “Adaptation versus selection: the origins of metastatic behavior,” Cancer Research, vol. 67, no. 24, pp. 11476–11480, 2007.
View at: Publisher Site | Google Scholar
J. J. Christiansen and A. K. Rajasekaran, “Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis,” Cancer Research, vol. 66, no. 17, pp. 8319–8326, 2006.
View at: Publisher Site | Google Scholar
P. A. Kenny, G. Y. Lee, and M. J. Bissell, “Targeting the tumor microenvironment,” Frontiers in Bioscience, vol. 12, pp. 3468–3474, 2007.
View at: Publisher Site | Google Scholar
R. M. Strieter, M. D. Burdick, J. Mestas, B. Gomperts, M. P. Keane, and J. A. Belperio, “Cancer CXC chemokine networks and tumour angiogenesis,” European Journal of Cancer, vol. 42, no. 6, pp. 768–778, 2006.
View at: Publisher Site | Google Scholar
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 Site | Google Scholar
Y. Bren-Mattison, A. M. Meyer, V. Van Putten et al., “Antitumorigenic effects of peroxisome proliferator-activated receptor- $?$ in non-small-cell lung cancer cells are mediated by suppression of cyclooxygenase-2 via inhibition of nuclear factor- $?$ B,” Molecular Pharmacology, vol. 73, no. 3, pp. 709–717, 2008.
View at: Publisher Site | Google Scholar
K. S. Lee, S. R. Kim, S. J. Park et al., “Peroxisome proliferator activated receptor- $?$ modulates reactive oxygen species generation and activation of nuclear factor- $?$ B and hypoxia-inducible factor 1 $a$ in allergic airway disease of mice,” Journal of Allergy and Clinical Immunology, vol. 118, no. 1, pp. 120–127, 2006.
View at: Publisher Site | Google Scholar
L. Gelman, L. Michalik, B. Desvergne, and W. Wahli, “Kinase signaling cascades that modulate peroxisome proliferator-activated receptors,” Current Opinion in Cell Biology, vol. 17, no. 2, pp. 216–222, 2005.
View at: Publisher Site | Google Scholar
M. Akaike, W. Che, N.-L. Marmarosh et al., “The hinge-helix 1 region of peroxisome proliferator-activated receptor $?$ 1 (PPAR $?$ 1) mediates interaction with extracellular signal-regulated kinase 5 and PPAR $?$ 1 transcriptional activation: involvement in flow-induced PPAR $?$ activation in endothelial cells,” Molecular and Cellular Biology, vol. 24, no. 19, pp. 8691–8704, 2004.
View at: Publisher Site | Google Scholar
R. A. Winn, L. Marek, S.-Y. Han et al., “Restoration of Wnt-7a expression reverses non-small cell lung cancer cellular transformation through Frizzled-9-mediated growth inhibition and promotion of cell differentiation,” Journal of Biological Chemistry, vol. 280, no. 20, pp. 19625–19634, 2005.
View at: Publisher Site | Google Scholar
R. A. Winn, M. Van Scoyk, M. Hammond et al., “Antitumorigenic effect of Wnt 7a and Fzd 9 in non-small cell lung cancer cells is mediated through ERK-5-dependent activation of peroxisome proliferator-activated receptor $?$ ,” Journal of Biological Chemistry, vol. 281, no. 37, pp. 26943–26950, 2006.
View at: Publisher Site | Google Scholar
M. Schirner and M. R. Schneider, “Inhibition of metastasis by cicaprost in rats with established SMT2A mammary carcinoma growth,” Cancer Detection and Prevention, vol. 21, no. 1, pp. 44–50, 1997.
View at: Google Scholar
K. V. Honn, B. Cicone, and A. Skoff, “Prostacyclin: a potent antimetastatic agent,” Science, vol. 212, no. 4500, pp. 1270–1272, 1981.
View at: Publisher Site | Google Scholar
R. L. Keith, Y. E. Miller, Y. Hoshikawa et al., “Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer,” Cancer Research, vol. 62, no. 3, pp. 734–740, 2002.
View at: Google Scholar
R. L. Keith, Y. E. Miller, T. M. Hudish et al., “Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice,” Cancer Research, vol. 64, no. 16, pp. 5897–5904, 2004.
View at: Publisher Site | Google Scholar
S. Narumiya, Y. Sugimoto, and F. Ushikubi, “Prostanoid receptors: structures, properties, and functions,” Physiological Reviews, vol. 79, no. 4, pp. 1193–1226, 1999.
View at: Google Scholar
E. Falcetti, D. M. Flavell, B. Staels, A. Tinker, S. G. Haworth, and L. H. Clapp, “IP receptor-dependent activation of PPAR $γ$ by stable prostacyclin analogues,” Biochemical and Biophysical Research Communications, vol. 360, no. 4, pp. 821–827, 2007.
View at: Publisher Site | Google Scholar
H. Lim and S. K. Dey, “PPAR $δ$ functions as a prostacyclin receptor in blastocyst implantation,” Trends in Endocrinology and Metabolism, vol. 11, no. 4, pp. 137–142, 2000.
View at: Publisher Site | Google Scholar
F. Y. Ali, K. Egan, G. A. FitzGerald et al., “Role of prostacyclin versus peroxisome proliferator-activated receptor $ß$ receptors in prostacyclin sensing by lung fibroblasts,” American Journal of Respiratory Cell and Molecular Biology, vol. 34, no. 2, pp. 242–246, 2006.
View at: Publisher Site | Google Scholar
M. A. Huber, N. Kraut, and H. Beug, “Molecular requirements for epithelial-mesenchymal transition during tumor progression,” Current Opinion in Cell Biology, vol. 17, no. 5, pp. 548–558, 2005.
View at: Publisher Site | Google Scholar
H. Peinado, D. Olmeda, and A. Cano, “Snail, zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?” Nature Reviews Cancer, vol. 7, no. 6, pp. 415–428, 2007.
View at: Publisher Site | Google Scholar
J. Yang, S. A. Mani, J. L. Donaher et al., “Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis,” Cell, vol. 117, no. 7, pp. 927–939, 2004.
View at: Publisher Site | Google Scholar
M.-H. Yang, M.-Z. Wu, S.-H. Chiou et al., “Direct regulation of TWIST by HIF-1 $a$ promotes metastasis,” Nature Cell Biology, vol. 10, no. 3, pp. 295–305, 2008.
View at: Publisher Site | Google Scholar
M. Dohadwala, S.-C. Yang, J. Luo et al., “Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin $E_{2}$ induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer,” Cancer Research, vol. 66, no. 10, pp. 5338–5345, 2006.
View at: Publisher Site | Google Scholar
L.-Q. Cao, X.-L. Chen, Q. Wang et al., “Upregulation of PTEN involved in rosiglitazone-induced apoptosis in human hepatocellular carcinoma cells,” Acta Pharmacologica Sinica, vol. 28, no. 6, pp. 879–887, 2007.
View at: Publisher Site | Google Scholar
S. Y. Lee, G. Y. Hur, K. H. Jung et al., “PPAR- $?$ agonist increase gefitinib's antitumor activity through PTEN expression,” Lung Cancer, vol. 51, no. 3, pp. 297–301, 2006.
View at: Publisher Site | Google Scholar
L. V. Madrid, C.-Y. Wang, D. C. Guttridge, A. J. G. Schottelius, A. S. Baldwin Jr., and M. W. Mayo, “Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF- $κ$ B,” Molecular and Cellular Biology, vol. 20, no. 5, pp. 1626–1638, 2000.
View at: Publisher Site | Google Scholar
J. A. Romashkova and S. S. Makarov, “NF- $κ$ B is a target of AKT in anti-apoptotic PDGF signalling,” Nature, vol. 401, no. 6748, pp. 86–90, 1999.
View at: Publisher Site | Google Scholar
N. Sizemore, S. Leung, and G. R. Stark, “Activation of phosphatidylinositol 3-kinase in response to interleukin- 1 leads to phosphorylation and activation of the NF- $κ$ B p65/RelA subunit,” Molecular and Cellular Biology, vol. 19, no. 7, pp. 4798–4805, 1999.
View at: Google Scholar
A. J. Dannenberg, N. K. Altorki, J. O. Boyle et al., “Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer,” Lancet Oncology, vol. 2, no. 9, pp. 544–551, 2001.
View at: Publisher Site | Google Scholar
S. Hazra, R. K. Batra, H. H. Tai, S. Sharma, X. Cui, and S. M. Dubinett, “Pioglitazone and rosiglitazone decrease prostaglandin $E_{2}$ in non-small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin dehydrogenase,” Molecular Pharmacology, vol. 71, no. 6, pp. 1715–1720, 2007.
View at: Publisher Site | Google Scholar
M. D. Castellone, H. Teramoto, B. O. Williams, K. M. Druey, and J. S. Gutkind, “Prostaglandin $E_{2}$ promotes colon cancer cell growth through a $G_{s}$ -axin- $β$ -catenin signaling axis,” Science, vol. 310, no. 5753, pp. 1504–1510, 2005.
View at: Publisher Site | Google Scholar
S. Han and J. Roman, “Suppression of prostaglandin $E_{2}$ receptor subtype EP2 by PPAR $γ$ ligands inhibits human lung carcinoma cell growth,” Biochemical and Biophysical Research Communications, vol. 314, no. 4, pp. 1093–1099, 2004.
View at: Publisher Site | Google Scholar

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Copyright © 2008 Raphael A. Nemenoff 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.

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