Review | Open Access
Vol.6 (2022) | Issue-1 | Page No: 1-8
Shixiong Wei1*
Affiliations + Expand
1. Department of Cardiothoracic Surgery, The First Bethune Hospital of Jilin University, Changchun, 130000, Jilin Province, China.
* Corresponding Author
Address for Correspondance: Dr.Shixiong Wei, The First Bethune Hospital of Jilin University, Changchun, No.1 Xinmin Road, Chaoyang District, Changchun, 130000, Jilin Province, China, email: wei_shixiong@163.com, Ph: +8613269330000
Important Dates + Expand
Date of Submission: 07-Jan-2022
Date of Acceptance: 28-Feb-2022
Date of Publication: 30-Mar-2022
Lung cancer is one of the main causes of cancer-related deaths. Clinically, most patients are diagnosed at the advanced stage of the disease, hence often confront poor prognosis. Therefore, it is crucial to develop new prevention and treatment methods. Peroxisome Proliferator-Activated Receptors (PPARs) are a class of nuclear transcription factors activated by ligands, belonging to the type II nuclear hormone receptor superfamily. PPAR-γ is known to promote differentiation, antiproliferation, and apoptosis in adipocyte maturation and lipid homeostasis. However, more and more evidences show that it also plays an important role in tumor inhibition. The secretion of certain metalloproteinases and extracellular matrix proteins, which may induce angiogenesis in the tumor matrix microenvironment, are regulated by PPAR-γ and thus can inhibit the development and metastasis of malignant tumors such as lung cancer. This article reviews the relevant literature, and summarizes the research progress of PPAR-γ agonists used alone or in combination with standard chemotherapy as new therapies for lung cancer.
Lung cancer accounts for about 25% of cancer-related deaths every year and can be classified into small cell lung cancer (SCLC) and Non-small cell lung cancer (NSCLC) according to their pathological manifestations. NSCLC comprising of adenocarcinoma, squamous cell carcinoma, and large cell carcinoma accounts for 85% of all lung cancers, while the remaining 15% is SCLC.[1],[2] Genetic mutation, poor diet, and air pollution are currently known risk factors for lung cancer, and chronic lung inflammation and infection have been demonstrated to play a role in the process.[3] Although medical technology has evolved significantly in the past 30 years, the overall 5-year survival rate of lung cancer patients is still less than 18%, which is mainly due to the fact that more than half of the patients are in the advanced stage at diagnosis.[4] Therefore, there is an urgent need for surgeons to follow new preventive, diagnostic, and therapeutic strategies to improve the clinical outcomes of patients with lung cancer.
Initially, cells acquire the ability to dedifferentiate or escape terminal differentiation, proliferate in an unrestricted manner and resist apoptosis, which in turn enables them to produce tumors. Therefore, interventions that reverse these processes have become one of the main research areas in cancer treatment. Studies have shown that activation of nuclear hormone receptors can produce therapeutic effects on several common tumors. In addition, agonists of estrogen receptor-β, retinoic acid receptor-α, and Retinoid X receptor (RXR) have also been shown to have pre-differentiation, anti-proliferation, and/or pro-apoptotic effects in a variety of cancers.[5] Peroxisome proliferator-activated receptors (PPARs), another type of nuclear hormone receptor, have long been recognized for their role in the regulation of lipid and glucose metabolism. However, recent studies have shown that the mechanism by which PPAR target genes are activated or inhibited by transcription also plays an important role in cell differentiation, proliferation, survival, and apoptosis-related carcinogenesis.[6],[7] PARs in the human body widely exist in a variety of cells. They are broadly
divided into three types; PPAR-α, PPAR-β/δ, and PPAR-γ, with each group differing in structure and function, as well as the expression of the site and pattern.[5],[7] Compared with the former two, PPAR-γ has a more active role in lung cancer tissues, so its research value as a tumor suppressor is also higher.[8]
Based on the variations in promoter sequence and splicing method, the mRNA of PPAR-γ can be divided into four subtypes: PPAR-γ1, PPAR-γ2, PPAR-γ3, and PPAR-γ4. PPAR-γ1 is the most important subtype of PPAR-γ, which is widely distributed in adipose tissues, the heart, pancreas, gastrointestinal tract, kidney, and skeletal muscle. The molecular structure of PPAR-γ2 is 30 amino acids longer than that of PPAR-γ1, and it is mainly expressed in adipose tissues, which exert multiple effects on human metabolism, insulin sensitization, and inflammatory response. PPAR-γ3 is expressed in adipocytes, macrophages, and colonic epithelial cells, while the tissue distribution of PPAR-γ4 is currently unclear.[7]
Previous studies have shown that PPAR-γ is widely present in tumor tissues of patients with SCLC and NSCLC.[9] However, due to some modification mechanism of the functional domain or the lack of suitable ligands, this receptor is inactive in lung cancer cells. In fact, studies have shown that the loss of PPAR-γ function in vivo may be related to the metastasis of colorectal cancer.[10] Immunohistochemical study of 147 primary NSCLC tumor specimens confirmed that the expression of PPAR-γ was related to the histological type and pathological grade of tumor specimens. Also, its expression in well-differentiated adenocarcinoma was much higher than that in poorly differentiated adenocarcinoma or squamous cell carcinoma, which provided a theoretical foundation to study the role of PPAR-γ in the treatment of lung cancer patients.[11]
It has been established that PPAR-γ ligands are both naturally occurring and artificially synthesized; the former includes saturated fatty acids, unsaturated fatty acids, and eicosane derivatives, such as 15-deoxy-δ 12, 14-prostaglandin J2 (15D-pgj2) and nitrated fatty acids such as nitrated linoleic acid and nitrated oleic acid, while the latter is a synthetic compound represented by thiazolidinediones (TZDs), such as Pioglitazone, Rosiglitazone, and Troglitazone.[8] At present, it is believed that these agonists can activate the PPAR-γ pathway through a variety of pathways, including direct binding to PPAR-γ ligand, binding to heat shock protein 72, and then binding to a ligand. However, the mainstream view is that the ligand first activates PPAR-γ by regulating the phosphorylation of tyrosine residues in kinases -1,2 by extracellular signals and the phosphorylation of mitogen-activated protein kinase (MAPK). It forms heterodimers (PPAR: RXR) with the corpus luteum X receptor and binds to specific peroxisome proliferator-response elements in the promoter region of the target gene, thereby activating the transcriptional activity of PPAR-γ.[12] A large number of evidence have shown that PPAR-γ agonists have an anti-tumor effect, which can limit their proliferation, growth, and progression, and induce their differentiation and apoptosis.[13] Therefore, PPAR-γ is worthy of investigation as a new approach to the treatment of lung cancer.
Multiple molecular mechanisms play role in the anti-tumor process of PPAR-γ activation, which not only affects cancer cells themselves but also affects the microenvironment of tumor cells, such as surrounding immune system cells, fibroblasts, fat cells, blood, and lymphatic system, etc. Studies have shown that apart from cellular components, PPAR-γ can even affect non-cellular components of the tumor microenvironment, such as growth factors, cytokines, chemokines, extracellular matrix (ECM), etc. PPAR-γ plays a key role in all stages of tumor genesis and development by directly acting on tumor cells and indirectly acting on the tumor cell microenvironment (Figure 2).[13] Up to now, studies have shown that PPAR-γ can regulate the differentiation, proliferation, apoptosis, and metastasis of cancer cells after activation, and finally form a microenvironment that is not conducive to tumor growth and development, and can inhibit tumor development and metastasis.
2.1. Role of PPAR-γ agonist in tumorigenesis
2.1.1. Regulatory effect of PPAR-γ agonist on tumor cells
PPAR-γ is an important regulator of cell differentiation and a key factor that represents the antitumor potential of the human body. As mentioned above, cells often dedifferentiate or escape terminal differentiation during carcinogenesis, so the expression of protein markers related to cell differentiation in cancer cells is usually down-regulated. Actin-binding protein (Gelsolin), one of such markers, is low in expression in many cancers, including lung cancer, and up-regulated after induction of differentiation in vitro. The PPAR-γ activation of Ciglitazone and 15d-PGJ2 in multiple non-small cell lung cancer cell lines enhanced the expression of gelsolin, Mad, and p21, suggesting that it promoted the differentiation process of cancer cells while also reducing the expression of lineage-specific markers associated with lung progenitor cells, such as mucin 1 (MUC1) and surfactant protein -A (SP-A). Moreover, the researchers also observed that the treatment with Ciglitazone could promote the morphological changes of cancer cells, and the treated cells were closer to differentiated and mature cells.[14] Another study further explored this finding, which proved that such PPAR-γ agonists can induce the differentiation of NSCLC cells of A549 and NCI-H23, with the continuous activation of extracellular signal-regulated kinase 1/2 (ERK1/2), which has been proved to be able to induce cell differentiation.[15] Other studies have shown that PPAR-γ activation can also induce adenocarcinoma cells to transform into polar mature differentiation phenotype.[16] These studies have proved the anti-tumor and pre-differentiation effects of PPAR-γ activator in lung cancer.
The activation of PPAR-γ can also inhibit abnormal cell proliferation and tumor growth, and promote tumor cell apoptosis. A variety of PPAR-γ ligands have shown this anti-tumor effect in a variety of lung cancer cell lines as well as in mouse lung cancer models, and interestingly, researchers observed that there may be a variety of mechanisms that depend on cell type specifically responsible for these anti-proliferative and pro-apoptotic effects of PPAR-γ agonists. Troglitazone can inhibit the growth and induce the apoptosis of SQ-5 NSCLC cells in a PPAR-γ-dependent manner by stimulating the transcription factor GADD153, which is involved in the pro-apoptotic process.[17] Similarly, Ciglitazone and 15d-PGJ2 inhibit cell proliferation and promote the apoptosis of SCLC cells of H345 and H2081 and NSCLC cells of H1838 and H2106. The researchers found that the potential mechanisms that play a role in this process are up-regulation of p21 expression and down-regulation of cyclin D1 expression.[18] Troglitazone is also capable of inhibiting NSCLC cell proliferation in H1838, H1792, and A549 through PPAR-γ mediated inhibition of phosphoinositide 3-kinase (PI3K)/Akt signal pathway, stimulating that expression of deleted phosphatase and tensin homologues on chromosome 10 (PTEN). In addition, the aggregation of G0/G1 phase cells and the reduction in the number of S-phase cells can also demonstrate that Troglitazone can exert antiproliferative effects by inducing the blockade of G0/G1 cells in multiple NSCLC cell lines.[19] In A549 cells, cell cycle arrest is caused by decreased expression of two G1 phase regulators, cyclins D, and E. Although the apoptotic pathway is not affected in A549 cells, Troglitazone-mediated growth inhibition is the result of increased caspases-3 and caspases-9-dependent apoptosis in NSCLC cells of NCI-H23.[20] Through studying the signaling pathways of these apoptotic processes, people found that the expression levels of B-cell lymphoma -2 (Bcl-2) and Bcl-w were decreased, while the continuous activation of ERK1/2 and p38 led to the decreased expression of stress-activated protein kinase (SAPK)/c-jun N-terminal kinase (JNK).[21] Finally, nonsteroidal anti-inflammatory drugs, as another type of PPAR-γ ligand, have also been shown to inhibit non-anchored growth in NSCLC and SCLC cells. Natural and synthetic PPAR-γ ligands, as well as PPAR overexpression studies, yielded similar results.[22]
The above studies are supported by the results of animal studies. Troglitazone and Pioglitazone as well as Sulindac sulfide significantly reduced the primary tumor growth of NSCLC cells in A549 in a xenogenic mouse model.[23] Moreover, in the research using a mouse model of spontaneous lung adenocarcinoma, the treatment with Troglitazone or Pioglitazone can significantly delay the disease progression. This ability to inhibit tumors from proliferation to metastasis is the result of inhibited cell proliferation.[24] Therefore, the pro-differentiation, anti-proliferation, and pro-apoptosis functions generated after the activation of PPAR-γ will make PPAR-γ agonists become drugs with the potential to treat lung cancer.
2.1.2. Regulatory effect of PPAR-γ agonist on tumor microenvironment
Neovascularization is a pathological process necessary for cancer cells to successfully produce primary and metastatic lesions. Neovascularization allows tumor growth beyond the limits imposed by passive oxygen and nutrient diffusion at the primary and secondary sites and promotes metastasis by providing access for cancer cells to enter the circulation. Under normal circumstances, the angiogenic process is affected by both angiogenic and antiangiogenic factors, however, the upregulation of angiogenic factors during tumorigenesis leads to persistent abnormal angiogenesis. Unlike normal blood vessels, these tumor-associated blood vessels are highly permeable, further promoting the local diffusion and distant metastasis of cancer cells.[25]
Vascular endothelial growth factor (VEGF) is currently recognized as a potent angiogenic factor,[1] and in addition, includes members of the CXC chemokine family containing ELR motifs such as interleukin-8 (IL- 8, CXCL8), epithelial neutrophil-activating protein 78 (ena-78, CXCL5), growth regulated oncogene-α (growth regulated oncogene-α, growth-α, CXCL1) all of which have been proved to be capable of induce angiogenesis by stimulating the chemotaxis of endothelial cells that form new blood vessels.[26] Rosiglitazone reduces the tumor burden in mice by reducing the secretion of VEGF and inhibiting angiogenesis in Lewis lung cancer (LLC) cells, while Troglitazone and Pioglitazone inhibit the neoangiogenesis in mouse xenogenic cancer cell transplantation model by inhibiting the secretion of ELR-positive CXC chemokines by A549 cells and the migration of endothelial cells.[27] The activation of PPAR-γ, which is highly expressed in tumor endothelial cells, not only affects angiogenesis by inhibiting angiogenic factors but also blocks angiogenesis by directly inhibiting endothelial cell growth.[28] In addition, 15d- PGJ2 has been proved to induce caspase-dependent apoptosis in endothelial cells, and its antiangiogenic effect is worthy of further investigation.[29]
Stromal cells, led by myofibroblasts, are the main sources of cytokines, growth factors, matrix metalloproteinases (MMP), and ECM proteins in the tumor microenvironment, providing important assistance in the growth and metastasis of tumors. The transforming growth factor-β (TGF-β) signaling pathway has the function of inducing fibroblast differentiation into myofibroblasts, while 15d- PGJ2, Troglitazone, Ciglitazone, and Rosiglitazone have been demonstrated to inhibit TGF-β-stimulated differentiation of primary human lung fibroblasts into myofibroblasts, which is also true in IMR-90 human fetal lung fibroblasts.[30],[31] In addition, TGF-β-induced fibronectin expression was also inhibited by the PPAR-γ agonist pioglitazone, which has replicated in PPAR-γ ligand BRL49653, 15d- PGJ2, or Troglitazone-treated H1838 NSCLC cells.[32],[33] Studies have shown that the abnormal increase of some ECM components, including fibronectin and type Ⅰ collagen, will trigger the remodeling of the tumor microenvironment and eventually lead to the generation and development of cancer.[34] Therefore, PPAR-γ agonists do have significant anti-tumor effects and have a positive impact on the tumor microenvironment, which can further support their role and value in the treatment of lung cancer.
2.2. Effect of PPAR-γ agonist on tumor metastasis
The effect of PPAR-γ on lung cancer is not just limited to the regulation of the formation and development of primary tumors. More and more evidences show that PPAR-γ can inhibit tumor metastasis after activation. In a study using a mouse xenogenic tumor cell transplantation model, the researchers found that the A549 cancer cell line transplanted to the dorsal side of the mouse was significantly inhibited after the application of Troglitazone or Pioglitazone. Another study has shown that metastases are detected in the lungs of animals treated with PPAR-γ agonists in a smaller and smaller number than those treated with placebo.[35] Similarly, a study using a rat model of in situ lung cancer showed that PPAR-γ overexpression was able to block the metastasis of tumor cells from one lung to the opposite lung or mediastinum by weakening the invasion ability of cancer cells, and the rats overexpressing PPAR-γ also survived for a longer period of time than the control rats.[36] Similar results were obtained in the mouse xenogeneic tumor cell transplantation model by implanting the LLC cell line into the subcutaneous area of the back of the mouse: Treatment with Rosiglitazone almost completely blocked the lung metastasis, thus retaining normal structure on most of the lung tissue, while the lung tissue of the control mice was full of metastatic cancer cells. Moreover, the researcher also observed the presence of LLC cells in the pulmonary vessels of mice treated with Rosiglitazone, but no LLC cells were detected in the lung parenchyma. These findings suggested that Rosiglitazone was able to inhibit the metastasis of tumor cells by preventing cancer cells from escaping into the circulation.[37]
Several other MMP experiments have also demonstrated the significant inhibitory effect of PPAR-γ agonists on tumor metastasis: matrix metalloproteinases are key regulators of extracellular matrix remodeling and destruction, and the expression of certain MMPs is related to the metastatic potential of tumors in mouse models and often to the poor prognosis of human patients with different types of cancer. In contrast, Rosiglitazone significantly reduced the activity of NCI-H157 and H1299 non-small cell lung cancer cells and the expression level of MMP-2,[14] and Rosiglitazone enhanced the activity of MMP tissue inhibitors, which substantially reduced the proteolytic activity of MMP.[38] Therefore, the inhibition of MMP also supports PPAR-γ-mediated antitumor effects.
The process of primary tumor metastasis is often accompanied by changes in the expression of some cell adhesion molecules. Naturally, E-cadherin connects epithelial cells together by secreting intercellular attachment molecules to maintain cells in a stable state. In tumor tissues, E-cadherin expression is often down-regulated, while adhesion molecules related to enhanced cell migration, such as N-cadherin, are usually up-regulated. Subsequently, intercellular adhesion loss, morphological changes, secretion of proteolytic enzymes, and anti-apoptosis appear. The activation of this process by tumor cells finally promotes their own diffusion and metastasis.[39]
TGF-β signaling pathway can drive and regulate a group of transcription factors including Snail, Slug, Twist, and zinc finger structure (ZEB1/2), and studies have shown that their expression in malignant tumors like lung cancer was abnormally increased, which has been proved to be related to the metastatic potential of advanced tumors and poor prognosis.[40] TGF-β could induce the formation of EMT in A549 cells, which was characterized by a gradual evolution from cuboidal epithelium to flat mesenchyme with loss of intercellular adhesion, as well as altered cadherin expression, which indicates enhanced tumor invasion and metastatic potential.[41] Troglitazone and Rosiglitazone could block TGF-β-induced EMT production, inhibit down-regulation of E-cadherin expression and up-regulation of N-cadherin and other mesenchymal cell markers. Furthermore, the researchers attempted to reverse the TGF-β-induced EMT production process using Troglitazone and Rosiglitazone and found that by inhibiting the transcriptional activity of SMAD3, a downstream component of TGF-β signal, both PPAR-γ agonists could maintain intercellular adhesion, inhibit the migration and invasion of tumor cells, and reduce the secretion of MMP-2 and MMP-9, further demonstrating the anti-tumor invasion and metastatic potential of PPAR-γ agonists.[13]
Clinical data showed that cancers diagnosed with local infiltration and distant metastasis are a strong predictor of poor prognosis. More than half of patients with lung cancer have distant metastasis at the time of diagnosis.[1] However, PPAR-γ agonists can not only inhibit the development of primary tumors but also inhibit their ability of infiltration and metastasis, which makes them have a broad prospect for treating lung cancer.
The potential value of PPAR-γ agonists in the treatment of lung cancer has not only been verified by a large number of experimental studies but also have been documented clinically. A multi-center study retrospectively analyzed 87,678 male patients with diabetes, of which, 11,289 patients used TZD while the remaining 76,389 patients did not use TZD. The study found that the probability of a subsequent diagnosis of lung cancer in the TZD group was decreased by 33%.[42] However, because of the study’s special population, it remains to be further explored for their application to the general population. One clinical trial (NCT00780234) targeting the general population is currently underway to evaluate the role of Pioglitazone in the prevention of lung cancer.
PPAR-γ agonists not only have a therapeutic effect on lung cancer when used alone but also show a good synergistic effect when used in combination with traditional chemotherapy drugs. Researchers combined PPAR-γ ligands such as Rosiglitazone and GW1929 with platinum drugs commonly used for the treatment of lung cancer such as cisplatin and carboplatin, and the results showed that they synergistically could inhibit the growth of NSCLC cell line. This effect was also evident in xenograft lung cancer models and spontaneous colon cancer models, with absence of additional toxicity to test animals. The mechanism of this synergistic effect is the activation of PPAR-γ which reduces the expression of metallothionein, thus protecting cells from platinum toxicity.[43] Another study using the PPAR-γ agonist Troglitazone and Pioglitazone in combination with the chemotherapeutic drugs cisplatin and paclitaxel has also obtained similar results in vivo.[44] In addition to traditional cytotoxic chemotherapy, specific molecular targeted therapy for tumorigenesis has attracted more and more attention from clinicians in recent years. PPAR-γ agonists also have synergistic effects with this new type of therapeutic agent. Rosiglitazone could enhance the anti-proliferative effect of epidermal growth factor receptor inhibitor gefitinib on A549 cells. The 3-hydroxy -3-methylglutaryl-CoA reductase (HMG-CoA reductase) inhibitor in combination with Troglitazone and lovastatin, inhibits the growth of CL1-0 lung adenocarcinoma cells significantly compared with the inhibitor alone.[45],[46]
Through the review of a large number of experimental data combined with clinical retrospective analysis data, it is clear that PPAR-γ has a good prospect as a new target of anticancer drugs. PPAR-γ agonists not only have a curative effect when used alone but also show a synergistic effect when used in combination with standard chemotherapy. All these have indicated that PPAR-γ agonist, in combination with other therapies that have been applied or are still in clinical trials, represents a novel and attractive therapeutic method for lung cancer. Researchers should continue to design multi-center randomized controlled clinical trials to verify the efficacy and safety of PPAR-γ agonists in the treatment of lung cancer.
FUNDING: N/A
CONFLICTS OF INTEREST:
The author confirms that there are no potential conflicts of interest.
1 | Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66(1):7-30. |
2 | Neal RD, Sun F, Emery JD, Callister ME. Lung cancer. BMJ June 2019:l1725. |
3 | Malhotra J, Malvezzi M, Negri E, La Vecchia C, Boffetta P. Risk factors for lung cancer worldwide. Eur Respir J 2016;48(3):889-902. |
4 | Wood DE, Kazerooni EA, Baum SL, Eapen GA, Ettinger DS, Hou L, Jackman DM, Klippenstein D, Kumar R, Lackner RP, Leard LE, Lennes IT, Leung ANC, Makani SS, Massion PP, Mazzone P, Merritt RE, Meyers BF, Midthun DE, Pipavath S, Pratt C, Reddy C, Reid ME, Rotter AJ, Sachs PB, Schabath MB, Schiebler ML, Tong BC, Travis WD, Wei B, Yang SC, Gregory KM, Hughes M. Lung Cancer Screening, Version 3.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018;16(4):412-41. |
5 | Reddy AT, Lakshmi SP, Reddy RC. PPARγ as a Novel Therapeutic Target in Lung Cancer. PPAR Res 2016;2016:8972570. |
6 | Mirza AZ, Althagafi II, Shamshad H. Role of PPAR receptor in different diseases and their ligands: Physiological importance and clinical implications. European Journal of Medicinal Chemistry 2019;166:502-13. |
7 | Zhigang W, Shunlin L. Research progress on the relationship between PPARγ and lung cancer. Modern Practical Medicine 2016;(4):476-78. |
8 | Heudobler D, Rechenmacher M, Lüke F, Vogelhuber M, Pukrop T, Herr W, Ghibelli L, Gerner C, Reichle A. Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue. IJMS 2018;19(11):3540. |
9 | Li M, Lee TW, Mok TSK, Warner TD, Yim APC, Chen GG. Activation of peroxisome proliferator-activated receptor-γ by troglitazone (TGZ) inhibits human lung cell growth. J Cell Biochem 2005;96(4):760-74. |
10 | Yun S-H, Roh M-S, Jeong J-S, Park J-I. Peroxisome proliferator-activated receptor γ coactivator-1α is a predictor of lymph node metastasis and poor prognosis in human colorectal cancer. Annals of Diagnostic Pathology 2018;33:11-16. |
11 | Giaginis C, Politi E, Alexandrou P, Sfiniadakis J, Kouraklis G, Theocharis S. 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. Pathol Oncol Res 2012;18(4):875-83. |
12 | Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem 2000;43(4):527-50. |
13 | Reka AK, Goswami MT, Krishnapuram R, Standiford TJ, Keshamouni VG. Molecular cross-regulation between PPAR-γ and other signaling pathways: implications for lung cancer therapy. Lung Cancer 2011;72(2):154-59. |
14 | Chang TH, Szabo E. Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor gamma in non-small cell lung cancer. Cancer Res 2000;60(4):1129-38. |
15 | Li M, Lee TW, Yim APC, Mok TSK, Chen GG. Apoptosis induced by troglitazone is both peroxisome proliferator-activated receptor-gamma- and ERK-dependent in human non-small lung cancer cells. J Cell Physiol 2006;209(2):428-38. |
16 | Bren-Mattison Y, Van Putten V, Chan D, Winn R, Geraci MW, Nemenoff RA. Peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC). Oncogene 2005;24(8):1412-22. |
17 | Fitch W, MacKenzie ET, Harper AM. Effects of decreasing arterial blood pressure on cerebral blood flow in the baboon. Influence of the sympathetic nervous system. Circ Res 1975;37(5):550-57. |
18 | Han S, Sidell N, Fisher PB, Roman J. Up-regulation of p21 gene expression by peroxisome proliferator-activated receptor gamma in human lung carcinoma cells. Clin Cancer Res 2004;10(6):1911-19. |
19 | Lee SY, Hur GY, Jung KH, Jung HC, Lee SY, Kim JH, Shin C, Shim JJ, In KH, Kang KH, Yoo SH. PPAR-gamma agonist increase gefitinib’s antitumor activity through PTEN expression. Lung Cancer 2006;51(3):297-301. |
20 | Li M, Lee TW, Yim APC, Mok TSK, Chen GG. Apoptosis induced by troglitazone is both peroxisome proliferator-activated receptor-gamma- and ERK-dependent in human non-small lung cancer cells. J Cell Physiol 2006;209(2):428-38. |
21 | Li M, Lee TW, Mok TSK, Warner TD, Yim APC, Chen GG. Activation of peroxisome proliferator-activated receptor-gamma by troglitazone (TGZ) inhibits human lung cell growth. J Cell Biochem 2005;96(4):760-74. |
22 | Wick M, Hurteau G, Dessev C, Chan D, Geraci MW, Winn RA, Heasley LE, Nemenoff RA. Peroxisome proliferator-activated receptor-gamma is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth. Mol Pharmacol 2002;62(5):1207-14. |
23 | Geraci MW. TARGETING THE PROSTACYCLIN/PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA AXIS IN LUNG CANCER CHEMOPREVENTION. Trans Am Clin Climatol Assoc 2018;129:48-55. |
24 | Lyon CM, Klinge DM, Do KC, Grimes MJ, Thomas CL, Damiani LA, March TH, Stidley CA, Belinsky SA. Rosiglitazone prevents the progression of preinvasive lung cancer in a murine model. Carcinogenesis 2009;30(12):2095-99. |
25 | Zavyalova MV, Denisov EV, Tashireva LA, Savelieva OE, Kaigorodova EV, Krakhmal NV, Perelmuter VM. Intravasation as a Key Step in Cancer Metastasis. Biochemistry Moscow 2019;84(7):762-72. |
26 | Strieter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J, Dzuiba J, Van Damme J, Walz A, Marriott D. The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem 1995;270(45):27348-57. |
27 | Keshamouni VG, Arenberg DA, Reddy RC, Newstead MJ, Anthwal S, Standiford TJ. PPAR-gamma activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer. Neoplasia 2005;7(3):294-301. |
28 | Panigrahy D, Singer S, Shen LQ, Butterfield CE, Freedman DA, Chen EJ, Moses MA, Kilroy S, Duensing S, Fletcher C, Fletcher JA, Hlatky L, Hahnfeldt P, Folkman J, Kaipainen A. PPARγ ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest 2002;110(7):923-32. |
29 | Bishop-Bailey D, Hla T. Endothelial cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-Delta12, 14-prostaglandin J2. J Biol Chem 1999;274(24):17042-48. |
30 | Reka AK, Goswami MT, Krishnapuram R, Standiford TJ, Keshamouni VG. Molecular cross-regulation between PPAR-γ and other signaling pathways: implications for lung cancer therapy. Lung Cancer 2011;72(2):154-59. |
31 | Milam JE, Keshamouni VG, Phan SH, Hu B, Gangireddy SR, Hogaboam CM, Standiford TJ, Thannickal VJ, Reddy RC. PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2008;294(5):L891-901. |
32 | Maeda A, Horikoshi S, Gohda T, Tsuge T, Maeda K, Tomino Y. 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 Biol Int 2005;29(6):422-28. |
33 | Han S, Ritzenthaler JD, Rivera HN, Roman J. Peroxisome proliferator-activated receptor-gamma ligands suppress fibronectin gene expression in human lung carcinoma cells: involvement of both CRE and Sp1. Am J Physiol Lung Cell Mol Physiol 2005;289(3):L419-428. |
34 | Fang M, Yuan J, Peng C, Li Y. Collagen as a double-edged sword in tumor progression. Tumour Biol 2014;35(4):2871-82. |
35 | Keshamouni VG, Reddy RC, Arenberg DA, Joel B, Thannickal VJ, Kalemkerian GP, Standiford TJ. Peroxisome proliferator-activated receptor-gamma activation inhibits tumor progression in non-small-cell lung cancer. Oncogene 2004;23(1):100-108. |
36 | Bren-Mattison Y, Van Putten V, Chan D, Winn R, Geraci MW, Nemenoff RA. Peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC). Oncogene 2005;24(8):1412-22. |
37 | Panigrahy D, Singer S, Shen LQ, Butterfield CE, Freedman DA, Chen EJ, Moses MA, Kilroy S, Duensing S, Fletcher C, Fletcher JA, Hlatky L, Hahnfeldt P, Folkman J, Kaipainen A. PPARγ ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest 2002;110(7):923-32. |
38 | Hsu H-T, Sung M-T, Lee C-C, Kuo Y-J, Chi C-W, Lee H-C, Hsia C-Y. Peroxisome Proliferator-Activated Receptor γ Expression Is Inversely Associated with Macroscopic Vascular Invasion in Human Hepatocellular Carcinoma. IJMS 2016;17(8):1226. |
39 | Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-74. |
40 | Jeon H-S, Jen J. TGF-beta signaling and the role of inhibitory Smads in non-small cell lung cancer. J Thorac Oncol 2010;5(4):417-19. |
41 | Keshamouni VG, Michailidis G, Grasso CS, Anthwal S, Strahler JR, Walker A, Arenberg DA, Reddy RC, Akulapalli S, Thannickal VJ, Standiford TJ, Andrews PC, Omenn GS. Differential protein expression profiling by iTRAQ-2DLC-MS/MS of lung cancer cells undergoing epithelial-mesenchymal transition reveals a migratory/invasive phenotype. J Proteome Res 2006;5(5):1143-54. |
42 | Govindarajan R, Ratnasinghe L, Simmons DL, Siegel ER, Midathada MV, Kim L, Kim PJ, Owens RJ, Lang NP. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 2007;25(12):1476-81. |
43 | Girnun GD, Naseri E, Vafai SB, Qu L, Szwaya JD, Bronson R, Alberta JA, Spiegelman BM. Synergy between PPARgamma ligands and platinum-based drugs in cancer. Cancer Cell 2007;11(5):395-406. |
44 | Reddy RC, Srirangam A, Reddy K, Chen J, Gangireddy S, Kalemkerian GP, Standiford TJ, Keshamouni VG. Chemotherapeutic drugs induce PPAR-gamma expression and show sequence-specific synergy with PPAR-gamma ligands in inhibition of non-small cell lung cancer. Neoplasia 2008;10(6):597-603. |
45 | Lee SY, Hur GY, Jung KH, Jung HC, Lee SY, Kim JH, Shin C, Shim JJ, In KH, Kang KH, Yoo SH. PPAR-gamma agonist increase gefitinib’s antitumor activity through PTEN expression. Lung Cancer 2006;51(3):297-301. |
46 | Yao C-J, Lai G-M, Chan C-F, Cheng A-L, Yang Y-Y, Chuang S-E. Dramatic synergistic anticancer effect of clinically achievable doses of lovastatin and troglitazone. Int J Cancer 2006;118(3):773-79. |
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Antonio Lucena‑Cacace1,2,3, Amancio Carnero1,2
Michael Zhang, Kelvin Zheng, Muhammad Choudhury, John Phillips, Sensuke Konno
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Ge Ren1,2,3, Yawei Zhang1,2, Lei Ren1,2
Qing Du1, Xiaoying Ji2, Guangjing Yin3, Dengxian Wei3, Pengcheng Lin1, Yongchang Lu1,
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Lei Zhang1, Guoyu Qiu2, Xiaohui Xu2, Yufeng Zhou3, Ruiming Chang4
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Xipeng Wang1,2, Mitsuteru Yokoyama2, Ping Liu3
Xiaohui Xu1, Guoyu Qiu1, Lupeng Ji2, Ruiping Ma3, Zilong Dang4, Ruling Jia1, Bo Zhao1
Mansoor C. Abdulla
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Ge Zengyu4, Li Zhou5
Guoyu Qiu1, Xiaohui Xu1, Lupeng Ji2, Ruiping Ma3, Zilong Dang4, Huan Yang5
Steven Lehrer1, Peter H. Rheinstein2
Umair Ali Khan Saddozai1, Qiang Wang1, Xiaoxiao Sun1, Yifang Dang1, JiaJia Lv1,2, Junfang Xin1, Wan Zhu3, Yongqiang Li1, Xinying Ji1, Xiangqian Guo1
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Min Jiang1#, Rui Zheng1#, Ling Shao1, Ning Yao2, Zhengmao Lu1*
Qiaoxin Lin1, Bin Liang1, Yangyang Li2, Ling Tian3*, Dianna Gu1*
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