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Zhang, J.; Tang, M.; Shang, J. PPARγ Modulators in Lung Cancer. Encyclopedia. Available online: (accessed on 16 April 2024).
Zhang J, Tang M, Shang J. PPARγ Modulators in Lung Cancer. Encyclopedia. Available at: Accessed April 16, 2024.
Zhang, Jiyun, Miru Tang, Jinsai Shang. "PPARγ Modulators in Lung Cancer" Encyclopedia, (accessed April 16, 2024).
Zhang, J., Tang, M., & Shang, J. (2024, February 19). PPARγ Modulators in Lung Cancer. In Encyclopedia.
Zhang, Jiyun, et al. "PPARγ Modulators in Lung Cancer." Encyclopedia. Web. 19 February, 2024.
PPARγ Modulators in Lung Cancer

Lung cancer is one of the most lethal malignancies worldwide. Peroxisome proliferator-activated receptor gamma (PPARγ, NR1C3) is a ligand-activated transcriptional factor that governs the expression of genes involved in glucolipid metabolism, energy homeostasis, cell differentiation, and inflammation. Multiple studies have demonstrated that PPARγ activation exerts anti-tumor effects in lung cancer through regulation of lipid metabolism, induction of apoptosis, and cell cycle arrest, as well as inhibition of invasion and migration. Interestingly, PPARγ activation may have pro-tumor effects on cells of the tumor microenvironment, especially myeloid cells. Recent clinical data has substantiated the potential of PPARγ agonists as therapeutic agents for lung cancer. Additionally, PPARγ agonists also show synergistic effects with traditional chemotherapy and radiotherapy. However, the clinical application of PPARγ agonists remains limited due to the presence of adverse side effects.

peroxisome proliferator-activated receptor gamma lung cancer agonists transcriptional activity

1. Structure of PPARγ

The PPARG gene gives rise to four transcripts by differential promoter usage and alternative splicing, which results in the production of PPARγ1 (encoded by PPARG1, PPARG3, PPARG4 mRNAs) and PPARγ2 (encoded by PPARG2 mRNA) isoforms [1][2][3][4]. PPARγ2 has the same sequence as PPARγ1, except for an additional 28 amino acids at its N-terminus [1]. PPARγ1 is ubiquitously abundant in many tissues, whereas PPARγ2 is preferably expressed in adipocytes.
PPARγ shares a typical NR domain structure composed of five domains: A/B, C, D, E, and F domain (Figure 1A) [5]. The N-terminal A/B domain is highly variable among the NR family, and harbors a ligand-independent transcriptional activation function region termed AF-1 that regulates PPARγ activation through interdomain coordination and phosphorylation [6][7]. The C domain, also known as the DNA-binding domain (DBD), is the most conserved part of NRs and consists of two zinc finger motifs with nine cysteines [6]. This domain specifically recognizes and binds to the PPAR response elements (PPRE) on the target gene promoter to initiate transcription after forming a heterodimer with the retinoic X receptor α (RXRα) [8][9]. The poorly conserved D domain serves as a flexible hinge that allows rotation between the DNA-binding and ligand-binding domains, as well as containing a nuclear localization signal [6]. The E domain, also named the ligand binding domain (LBD), is the largest region of PPARγ and has four main functions, including a second dimerization interface, the ligand binding pocket, a coregulator binding surface, and ligand-dependent activation function referred to as AF-2 [10]. The C-terminal F domain is relatively small, and may contribute to interaction with cofactors [11].
Figure 1. Domain organization of PPARγ (A) and schematic of agonist binding with PPARγ LBD (PDB code: 6ONJ and 6DGL) (B).
Among PPARγ domain structures, the LBD was the first one to be characterized in conformation [12]. The PPARγ LBD consists of 13 α-helices (termed helix 1–12 and helix 2′) arranged in a three-layered sandwich and a small four-stranded β-sheet. The ligand binding pocket is located in the center of the LBD, and has a large Y- or T-shaped cavity with three branches [10]. Branch I is composed of helix3, helix5, helix11, and helix12 in the C-terminal AF-2 region; branch II is positioned around helix2′, helix3, helix6, helix7, and the β-sheet region; while branch III is surrounded by the β-sheet, helix2, helix3, and helix5. Adjacent to the ligand-binding pocket, there is an AF-2 coregulator interaction surface formed by the three-dimensional association of helix3, helix4, helix5, and helix12 [12][13].

2. Transcriptional Activities of PPARγ

PPARγ regulates gene expression through transactivation and transrepression. In the absence of ligands, PPARγ-RXRα heterodimer binds to PPREs and subsequently recruits corepressors and associated chromatin-modifying enzymes to silence target gene transcription, a process known as ligand-independent repression [14]. Once the ligand binds to PPARγ, the PPARγ-RXRα heterodimer undergoes a conformational change that releases corepressors in exchange for coactivators, resulting in the transcription of target genes. Furthermore, PPARγ can also negatively regulate gene expression in a ligand-dependent manner by antagonizing other transcription factors, such as nuclear factor-κB and activator protein-1 [15].

3. Dynamic Mechanisms of Ligand Binding Agonism

In the absence of ligands, helix 12 acts as a highly flexible switching element in equilibrium between many different conformations, ranging from active to repressive (Figure 1B) [16][17]. Agonists stabilize helix 12 in a conformation that exposes the AF-2 surface for the binding of coregulators that control target genes transcription [18]. Full PPARγ agonists stabilize an active AF-2 surface conformation via forming a critical hydrogen bond with Y473 residues on helix 12, facilitating the recruitment and binding of coactivators [19]. Partial agonists generally do not form hydrogen bonds with the key residues of the AF-2 regions, including Y473, but mildly stabilize helix 12 through interactions with other regions of the ligand-binding pocket, resulting in differential coactivator recruitment profiles and weak transcriptional activation compared to full agonists [10][20][21]. In contrast, inverse agonists exert transcriptional repression via stabilizing in a conformation that favors the recruitment of corepressors. However, the structural mechanism underlying the ligand-induced repression state is limited. Brust et al. identified R288 as the critical corepressor-selective inverse agonist (T0070907) switch residue, and found that T0070907-bound PPARγ exchanges between two long-lived conformations, one similar to the coactivator-bound state and the other similar to the corepressor-bound state [22]. Subsequently, the researchers' study further verified the structurally diverse mechanism of the inverse agonist-bound state and revealed the mechanism of action of T0070907 [16]. Briefly, T0070907 can stabilize helix 12 within the orthosteric pocket by pointing the pyridyl group toward the AF-2 surface, thereby increasing corepressor binding affinity.
The preceding section has provided a description of the binding modes demonstrated by various agonists. Subsequently, the dynamic changes in agonist binding with PPARγ LBD will be outlined below. Prior studies remain controversial as to whether ligand binding proceeds through induced fitting or conformational selection mechanisms. Notably, the researchers' recent study supported the existence of the induced fit mechanism involving a two-step process of an initial ligand encounter complex followed by a conformational change (Figure 1B) [23]. In the absence of ligand, helix 12 in apo-PPARγ LBD exchanges between transcriptionally repressive and a solvent-exposed active conformation through entering and exiting the orthosteric ligand-binding pocket. Agonist binds to the ligand entry site via an initial fast step to form an encounter complex, and this process can occur to either of these conformations. Subsequently, the agonist slowly enters the orthosteric ligand-binding pocket and forms the final ligand-binding pose. In this step, agonist binding to the repressive LBD conformation (helix 12 within the orthosteric pocket) would push helix 12 into an active conformation, while agonist binding to the active LBD conformation (helix 12 outside the orthosteric pocket) would facilitate transition into the final ligand-binding pose.

4. Role of PPARγ Activation in Lung Cancer

4.1. Regulation of Lipid Metabolism

Metabolic reprogramming is a crucial hallmark of malignancy, allowing tumor cells to meet demands for growth, proliferation, and metastasis, as well as be robust against unfavorable environments [24][25]. Thus, targeting abnormal tumor metabolic activities, including lipid metabolism, is a rapidly emerging direction for anti-cancer therapy [26]. PPARγ is a central regulator of lipid metabolism. Several studies have shown that PPARγ upregulates fatty acid synthesis and β-oxidation in lung cancer (Figure 2). For example, Phan et al. found that pioglitazone-mediated PPARγ activation induced de novo fatty acid synthesis and β-oxidation in lung cancer [27]. Importantly, dramatic lipid synthesis could deplete nicotinamide adenine dinucleotide phosphate (NADPH), a major reducing agent important for cellular anti-oxidation systems, leading to disrupted redox balance which, in turn, suppresses lung cancer. Moreover, Andela et al. reported a shift in cellular energy metabolism towards fatty acid oxidation in the lung alveolar carcinoma cell line via treatment with PPARγ agonist troglitazone [28].
Figure 2. Role of PPARγ activation in lung cancer cells. PPARγ, peroxisome proliferator-activated receptor gamma; RXRα, retinoic X receptor α; PPRE, PPAR response elements; GADD153, DNA-damage inducible gene 153; NADPH, nicotinamide adenine dinucleotide phosphate; ALDH, aldehyde dehydrogenases; ROS, reactive oxygen species; POX, proline oxidase; PTEN, phosphatase and tensin homolog; ERK1/2, extracellular signal-regulated protein kinases 1 and 2; cyt-c, mitochondrial cytochrome c; EMT, epithelial-mesenchymal transition; MMP-9, matrix metalloproteinase 9; HPA, heparanase; ICAM-1, intercellular adhesion molecule-1; VEGF, vascular endothelial growth factor.
Aldehyde dehydrogenases (ALDHs) act as an ‘aldehyde scavenger’ during lipid peroxidation and exhibit high activity in lung cancer [29][30]. Inhibition of ALDHs can expose cancer cells to highly reactive and toxic aldehydes, resulting in cell damage and apoptosis [31]. Notably, PPARγ has been reported to downregulate certain members of the ALDH family to function as a lung cancer inhibitor. For instance, arachidonic acid-induced PPARγ activation suppressed the growth of A549 cells through increasing lipid peroxidation and decreasing ALDH3A1 expression [32]. Additionally, TZD-mediated PPARγ activation inhibited ALDH1A3 expression to exert anti-proliferative functions in H1993 cells [33].

4.2. Promotion of Cell Apoptosis

Apoptosis is a homeostatic mechanism to maintain cell populations in normal tissues, whereas tumor cells engage various mechanisms to evade apoptosis for unrestricted proliferation [34][35]. Classical pathways of apoptosis include the intrinsic mitochondrial pathway and the extrinsic pathway that induces via the activation of death receptors on the cell surface, both of which result in the activation of cysteine aspartyl-specific proteases (also known as Caspases) to cleave several proteins leading to cell death [36][37]. PPARγ promotes apoptosis in lung cancer through dysregulating critical factors in these pathways (Figure 2). Specifically, PPARγ activation could increase the expression of pro-apoptotic factors Bax and Bad, decrease the expression of anti-apoptotic factors Bcl-2 and Bcl-XL, enhance caspase3 and caspase9 activity, and trigger mitochondrial cytochrome c release [38][39][40][41][42][43]. Furthermore, PPARγ activation enhanced TRAIL-induced apoptosis in human lung adenocarcinoma cells via autophagy flux [44]. Notably, PPARγ is also able to regulate the upstream signaling pathways to provoke apoptosis. For instance, KR-62980 or rosiglitazone-mediated PPARγ activation promoted the generation of reactive oxygen species (ROS) via proline oxidase (POX) induction, leading to apoptotic cell death in NSCLC [45]. Troglitazone-mediated PPARγ activation induced the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and subsequently caused apoptosis in NCI-H23 lung cancer cells via a mitochondrial pathway [46]. Another study showed that troglitazone-mediated PPARγ activation stimulated the expression of DNA-damage inducible gene 153 (GADD153) to trigger growth arrest and endoplasmic reticulum stress-induced apoptosis of NSCLC cells [47]. PPARγ agonist efatutazone could induce the cell cycle arrest and apoptosis of EGFR-TKI-resistant lung adenocarcinoma cells via PPARγ/phosphatase and tensin homolog (PTEN)/Akt pathway [48].

4.3. Induction of Cell Cycle Arrest

Cell division is tightly regulated by multiple conserved cell cycle control mechanisms, such as cyclins and cyclin-dependent kinases (CDKs), G1-S transcriptional regulation, DNA damage checkpoint, DNA replication stress checkpoint, and spindle assembly checkpoint [49]. The eukaryotic cell cycle can be divided into G0, G1, S, G2, and M phases. DNA replicates during the S phase and cell separates during the M phase. Several lines of evidence have shown that PPARγ is involved in cell cycle processes to induce the growth arrest of lung cancer cells (Figure 2). Troglitazone-mediated PPARγ activation could induce cell cycle arrest in the G0/G1 phase by downregulation of cyclins D and E [50]. The PPARγ ligands PGJ2, ciglitazone, troglitazone, and GW1929 suppressed human lung carcinoma cell growth by stimulating cyclin-dependent kinase inhibitor p21 expression and reducing cyclin D1 expression [51].

4.4. Inhibition of Tumor Metastasis

Metastasis is the cause of 90% of cancer-related deaths [52]. In the process of metastasis, normal cells transform into carcinogenic cells that proliferate uncontrollably, evade the immune system, resist programmed cell death, stimulate angiogenesis, acquire invasive potential, survive in the bloodstream, and establish cancerous growth in distant organs [53]. Epithelial–mesenchymal transition (EMT), a process through which epithelial cells lose apical–basal polarity, and cell–cell junctions, as well as attain a mesenchymal phenotype with invasive and migratory capabilities, is a critical event in the initiation of metastasis [53][54]. The mechanism of PPARγ in lung cancer-related EMT is not yet fully understood. Multiple studies have shown that PPARγ can regulate the expression of EMT-related molecules to exert an inhibitory effect on metastasis (Figure 2). Specifically, PPARγ activation increased expression of epithelial marker E-cadherin, decreased expression of mesenchymal marker N-cadherin, Snail, and fibronectin, as well as down-regulated expression of matrix metalloproteinase 9 (MMP-9) and heparanase (HPA) [55][56][57][58][59]. Moreover, PPARγ activation could also suppress the expression of invasion-related proteins, such as intercellular adhesion molecule-1 (ICAM-1) and C-X-C chemokine receptor type 4 (CXCR4), which function as facilitators in EMT [56][57][59].
Angiogenesis is the major route by which cancer cells spread from the primary tumor to other sites [53]. Tumor angiogenesis is regulated by both pro- and anti-angiogenic factors, and an imbalance between the two can lead to malformation of the vasculature with excessive branching, hyperpermeability, and leakage [53][60]. PPARγ has been reported to be involved in regulating angiogenic factors (Figure 2). For instance, PPARγ activation could inhibit angiogenesis by blocking the production of ELR + CXC chemokines in NSCLC [61]. Moreover, vascular endothelial growth factor (VEGF) was drastically downregulated through the PPARγ/NF-κB signaling pathway in human lung carcinoma 95D cells [40].

4.5. Influence on Tumor Immunity

The role of PPARγ activation in lung cancer immunity remains a controversial issue, which may correlate with the complexity of the immune microenvironment. Notably, the tumor microenvironment encompasses not only malignant cells, but also stromal cells, vascular endothelial cells, as well as various types of immune cells including tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) [62]. Interestingly, PPARγ seems to have opposing effects on cancer progression among different cells, with anti-oncogenic effects on cancer cells but pro-oncogenic effects on cancer-associated immune cells [63][64]. Gou et al. found that PPARγ inhibits the tumor immune escape by inducing PD-L1 autophagic degradation in NSCLC cells [65]. Interestingly, this process was independent of the transcriptional activity of PPARγ, but rather formed autophagy receptors through the binding of PPARγ to microtubule-associated protein 1A/1B-light chain 3 (LC3), leading to degradation of PD-L1 in lysosomes. Nevertheless, Li et al. suggested that PPARγ activation in myeloid cells promoted lung cancer progression and metastasis [63].


  1. Fajas, L.; Auboeuf, D.; Raspé, E.; Schoonjans, K.; Lefebvre, A.M.; Saladin, R.; Najib, J.; Laville, M.; Fruchart, J.C.; Deeb, S.; et al. The organization, promoter analysis, and expression of the human PPARgamma gene. J. Biol. Chem. 1997, 272, 18779–18789.
  2. Fajas, L.; Fruchart, J.C.; Auwerx, J. PPARgamma3 mRNA: A distinct PPARgamma mRNA subtype transcribed from an independent promoter. FEBS Lett. 1998, 438, 55–60.
  3. Sundvold, H.; Lien, S. Identification of a novel peroxisome proliferator-activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalpha1. Biochem. Biophys. Res. Commun. 2001, 287, 383–390.
  4. Tontonoz, P.; Hu, E.; Graves, R.A.; Budavari, A.I.; Spiegelman, B.M. mPPAR gamma 2: Tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994, 8, 1224–1234.
  5. Blanquart, C.; Barbier, O.; Fruchart, J.C.; Staels, B.; Glineur, C. Peroxisome proliferator-activated receptors: Regulation of transcriptional activities and roles in inflammation. J. Steroid Biochem. Mol. Biol. 2003, 85, 267–273.
  6. Aranda, A.; Pascual, A. Nuclear hormone receptors and gene expression. Physiol. Rev. 2001, 81, 1269–1304.
  7. Shao, D.; Rangwala, S.M.; Bailey, S.T.; Krakow, S.L.; Reginato, M.J.; Lazar, M.A. Interdomain communication regulating ligand binding by PPAR-gamma. Nature 1998, 396, 377–380.
  8. Guan, Y.; Breyer, M.D. Peroxisome proliferator-activated receptors (PPARs): Novel therapeutic targets in renal disease. Kidney Int. 2001, 60, 14–30.
  9. Chandra, V.; Huang, P.; Hamuro, Y.; Raghuram, S.; Wang, Y.; Burris, T.P.; Rastinejad, F. Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA. Nature 2008, 456, 350–356.
  10. Kroker, A.J.; Bruning, J.B. Review of the Structural and Dynamic Mechanisms of PPARγ Partial Agonism. PPAR Res. 2015, 2015, 816856.
  11. Danielian, P.S.; White, R.; Lees, J.A.; Parker, M.G. Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO J. 1992, 11, 1025–1033.
  12. Nolte, R.T.; Wisely, G.B.; Westin, S.; Cobb, J.E.; Lambert, M.H.; Kurokawa, R.; Rosenfeld, M.G.; Willson, T.M.; Glass, C.K.; Milburn, M.V. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 1998, 395, 137–143.
  13. Frkic, R.L.; Marshall, A.C.; Blayo, A.L.; Pukala, T.L.; Kamenecka, T.M.; Griffin, P.R.; Bruning, J.B. PPARγ in Complex with an Antagonist and Inverse Agonist: A Tumble and Trap Mechanism of the Activation Helix. iScience 2018, 5, 69–79.
  14. Hernandez-Quiles, M.; Broekema, M.F.; Kalkhoven, E. PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action. Front. Endocrinol. 2021, 12, 624112.
  15. Ricote, M.; Glass, C.K. PPARs and molecular mechanisms of transrepression. Biochim. Biophys. Acta 2007, 1771, 926–935.
  16. Shang, J.; Mosure, S.A.; Zheng, J.; Brust, R.; Bass, J.; Nichols, A.; Solt, L.A.; Griffin, P.R.; Kojetin, D.J. A molecular switch regulating transcriptional repression and activation of PPARγ. Nat. Commun. 2020, 11, 956.
  17. Kallenberger, B.C.; Love, J.D.; Chatterjee, V.K.; Schwabe, J.W. A dynamic mechanism of nuclear receptor activation and its perturbation in a human disease. Nat. Struct. Biol. 2003, 10, 136–140.
  18. Brzozowski, A.M.; Pike, A.C.; Dauter, Z.; Hubbard, R.E.; Bonn, T.; Engström, O.; Ohman, L.; Greene, G.L.; Gustafsson, J.A.; Carlquist, M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997, 389, 753–758.
  19. Johnson, B.A.; Wilson, E.M.; Li, Y.; Moller, D.E.; Smith, R.G.; Zhou, G. Ligand-induced stabilization of PPARgamma monitored by NMR spectroscopy: Implications for nuclear receptor activation. J. Mol. Biol. 2000, 298, 187–194.
  20. Bruning, J.B.; Chalmers, M.J.; Prasad, S.; Busby, S.A.; Kamenecka, T.M.; He, Y.; Nettles, K.W.; Griffin, P.R. Partial agonists activate PPARgamma using a helix 12 independent mechanism. Structure 2007, 15, 1258–1271.
  21. Hughes, T.S.; Chalmers, M.J.; Novick, S.; Kuruvilla, D.S.; Chang, M.R.; Kamenecka, T.M.; Rance, M.; Johnson, B.A.; Burris, T.P.; Griffin, P.R.; et al. Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism. Structure 2012, 20, 139–150.
  22. Brust, R.; Shang, J.; Fuhrmann, J.; Mosure, S.A.; Bass, J.; Cano, A.; Heidari, Z.; Chrisman, I.M.; Nemetchek, M.D.; Blayo, A.L.; et al. A structural mechanism for directing corepressor-selective inverse agonism of PPARγ. Nat. Commun. 2018, 9, 4687.
  23. Shang, J.; Kojetin, D.J. Structural mechanism underlying ligand binding and activation of PPARγ. Structure 2021, 29, 940–950.e944.
  24. Yoshida, G.J. Metabolic reprogramming: The emerging concept and associated therapeutic strategies. J. Exp. Clin. Cancer Res. CR 2015, 34, 111.
  25. Faubert, B.; Solmonson, A.; DeBerardinis, R.J. Metabolic reprogramming and cancer progression. Science 2020, 368, eaaw5473.
  26. Phan, L.M.; Yeung, S.C.; Lee, M.H. Cancer metabolic reprogramming: Importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol. Med. 2014, 11, 1–19.
  27. Phan, A.N.H.; Vo, V.T.A.; Hua, T.N.M.; Kim, M.K.; Jo, S.Y.; Choi, J.W.; Kim, H.W.; Son, J.; Suh, Y.A.; Jeong, Y. PPARγ sumoylation-mediated lipid accumulation in lung cancer. Oncotarget 2017, 8, 82491–82505.
  28. Andela, V.B.; Altuwaijri, S.; Wood, J.; Rosier, R.N. Inhibition of beta-oxidative respiration is a therapeutic window associated with the cancer chemo-preventive activity of PPARgamma agonists. FEBS Lett. 2005, 579, 1765–1769.
  29. Singh, S.; Brocker, C.; Koppaka, V.; Chen, Y.; Jackson, B.C.; Matsumoto, A.; Thompson, D.C.; Vasiliou, V. Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic. Biol. Med. 2013, 56, 89–101.
  30. Pors, K.; Moreb, J.S. Aldehyde dehydrogenases in cancer: An opportunity for biomarker and drug development? Drug Discov. Today 2014, 19, 1953–1963.
  31. Dinavahi, S.S.; Bazewicz, C.G.; Gowda, R.; Robertson, G.P. Aldehyde Dehydrogenase Inhibitors for Cancer Therapeutics. Trends Pharmacol. Sci. 2019, 40, 774–789.
  32. Muzio, G.; Trombetta, A.; Maggiora, M.; Martinasso, G.; Vasiliou, V.; Lassen, N.; Canuto, R.A. Arachidonic acid suppresses growth of human lung tumor A549 cells through down-regulation of ALDH3A1 expression. Free. Radic. Biol. Med. 2006, 40, 1929–1938.
  33. Hua, T.N.M.; Namkung, J.; Phan, A.N.H.; Vo, V.T.A.; Kim, M.K.; Jeong, Y.; Choi, J.W. PPARgamma-mediated ALDH1A3 suppression exerts anti-proliferative effects in lung cancer by inducing lipid peroxidation. J. Recept. Signal Transduct. Res. 2018, 38, 191–197.
  34. Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007, 35, 495–516.
  35. Sharma, A.; Boise, L.H.; Shanmugam, M. Cancer Metabolism and the Evasion of Apoptotic Cell Death. Cancers 2019, 11, 1144.
  36. Nicholson, D.W.; Thornberry, N.A. Caspases: Killer proteases. Trends Biochem. Sci. 1997, 22, 299–306.
  37. Reed, J.C. Apoptosis-targeted therapies for cancer. Cancer Cell 2003, 3, 17–22.
  38. Ge, L.N.; Yan, L.; Li, C.; Cheng, K. Bavachinin exhibits antitumor activity against non-small cell lung cancer by targeting PPARγ. Mol. Med. Rep. 2019, 20, 2805–2811.
  39. Li, M.Y.; Hsin, M.K.; Yip, J.; Mok, T.S.; Underwood, M.J.; Chen, G.G. PPARgamma activation extinguishes smoking carcinogen by inhibiting NNK-mediated proliferation. Am. J. Respir. Cell Mol. Biol. 2010, 42, 113–122.
  40. Liu, Y.; Tian, Y.; Cai, W.; Guo, Y.; Xue, C.; Wang, J. DHA/EPA-Enriched Phosphatidylcholine Suppresses Tumor Growth and Metastasis via Activating Peroxisome Proliferator-Activated Receptor γ in Lewis Lung Cancer Mice. J. Agric. Food Chem. 2021, 69, 676–685.
  41. Yue, H.; Tian, Y.; Zhao, Z.; Bo, Y.; Guo, Y.; Wang, J. Comparative Study of Docosahexaenoic Acid with Different Molecular Forms for Promoting Apoptosis of the 95D Non-Small-Cell Lung Cancer Cells in a PPARγ-Dependent Manner. Mar. Drugs 2022, 20, 599.
  42. Kim, T.W.; Hong, D.W.; Kang, C.M.; Hong, S.H. A novel PPARɣ ligand, PPZ023, overcomes radioresistance via ER stress and cell death in human non-small-cell lung cancer cells. Exp. Mol. Med. 2020, 52, 1730–1743.
  43. Kim, T.W.; Hong, D.W.; Hong, S.H. CB13, a novel PPARγ ligand, overcomes radio-resistance via ROS generation and ER stress in human non-small cell lung cancer. Cell Death Dis. 2020, 11, 848.
  44. Nazim, U.M.; Moon, J.H.; Lee, Y.J.; Seol, J.W.; Park, S.Y. PPARγ activation by troglitazone enhances human lung cancer cells to TRAIL-induced apoptosis via autophagy flux. Oncotarget 2017, 8, 26819–26831.
  45. Kim, K.Y.; Ahn, J.H.; Cheon, H.G. Apoptotic action of peroxisome proliferator-activated receptor-gamma activation in human non small-cell lung cancer is mediated via proline oxidase-induced reactive oxygen species formation. Mol. Pharmacol. 2007, 72, 674–685.
  46. Li, M.; Lee, T.W.; Yim, A.P.; Mok, T.S.; Chen, G.G. 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, 428–438.
  47. Satoh, T.; Toyoda, M.; Hoshino, H.; Monden, T.; Yamada, M.; Shimizu, H.; Miyamoto, K.; Mori, M. Activation of peroxisome proliferator-activated receptor-gamma stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells. Oncogene 2002, 21, 2171–2180.
  48. Ni, J.; Zhou, L.L.; Ding, L.; Zhao, X.; Cao, H.; Fan, F.; Li, H.; Lou, R.; Du, Y.; Dong, S.; et al. PPARγ agonist efatutazone and gefitinib synergistically inhibit the proliferation of EGFR-TKI-resistant lung adenocarcinoma cells via the PPARγ/PTEN/Akt pathway. Exp. Cell Res. 2017, 361, 246–256.
  49. Matthews, H.K.; Bertoli, C.; de Bruin, R.A.M. Cell cycle control in cancer. Nat. Rev. Mol. Cell Biol. 2022, 23, 74–88.
  50. Keshamouni, V.G.; Reddy, R.C.; Arenberg, D.A.; Joel, B.; Thannickal, V.J.; Kalemkerian, G.P.; Standiford, T.J. Peroxisome proliferator-activated receptor-gamma activation inhibits tumor progression in non-small-cell lung cancer. Oncogene 2004, 23, 100–108.
  51. Han, S.; Sidell, N.; Fisher, P.B.; Roman, J. Up-regulation of p21 gene expression by peroxisome proliferator-activated receptor gamma in human lung carcinoma cells. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2004, 10, 1911–1919.
  52. Mehlen, P.; Puisieux, A. Metastasis: A question of life or death. Nat. Rev. Cancer 2006, 6, 449–458.
  53. Castaneda, M.; den Hollander, P.; Kuburich, N.A.; Rosen, J.M.; Mani, S.A. Mechanisms of cancer metastasis. Semin. Cancer Biol. 2022, 87, 17–31.
  54. Fares, J.; Fares, M.Y.; Khachfe, H.H.; Salhab, H.A.; Fares, Y. Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduct. Target. Ther. 2020, 5, 28.
  55. Reka, A.K.; Kurapati, H.; Narala, V.R.; Bommer, G.; Chen, J.; Standiford, T.J.; Keshamouni, V.G. Peroxisome proliferator-activated receptor-gamma activation inhibits tumor metastasis by antagonizing Smad3-mediated epithelial-mesenchymal transition. Mol. Cancer Ther. 2010, 9, 3221–3232.
  56. Li, J.; Chen, L.; Yu, P.; Liu, B.; Zhu, J.; Yang, Y. Telmisartan exerts anti-tumor effects by activating peroxisome proliferator-activated receptor-γ in human lung adenocarcinoma A549 cells. Molecules 2014, 19, 2862–2876.
  57. Yin, H.; Liu, Y.; Yue, H.; Tian, Y.; Dong, P.; Xue, C.; Zhao, Y.T.; Zhao, Z.; Wang, J. DHA- and EPA-Enriched Phosphatidylcholine Suppress Human Lung Carcinoma 95D Cells Metastasis via Activating the Peroxisome Proliferator-Activated Receptor γ. Nutrients 2022, 14, 4675.
  58. Choudhary, R.; Li, H.; Winn, R.A.; Sorenson, A.L.; Weiser-Evans, M.C.; Nemenoff, R.A. Peroxisome proliferator-activated receptor-gamma inhibits transformed growth of non-small cell lung cancer cells through selective suppression of Snail. Neoplasia 2010, 12, 224–234.
  59. Han, S.; Ritzenthaler, J.D.; Rivera, H.N.; 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, L419–L428.
  60. Lugano, R.; Ramachandran, M.; Dimberg, A. Tumor angiogenesis: Causes, consequences, challenges and opportunities. Cell. Mol. Life Sci. 2020, 77, 1745–1770.
  61. Keshamouni, V.G.; Arenberg, D.A.; Reddy, R.C.; Newstead, M.J.; Anthwal, S.; Standiford, T.J. PPAR-gamma activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer. Neoplasia 2005, 7, 294–301.
  62. Jin, M.Z.; Jin, W.L. The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct. Target. Ther. 2020, 5, 166.
  63. Li, H.; Sorenson, A.L.; Poczobutt, J.; Amin, J.; Joyal, T.; Sullivan, T.; Crossno, J.T., Jr.; Weiser-Evans, M.C.; Nemenoff, R.A. Activation of PPARγ in myeloid cells promotes lung cancer progression and metastasis. PLoS ONE 2011, 6, e28133.
  64. Cheng, H.S.; Yip, Y.S.; Lim, E.K.Y.; Wahli, W.; Tan, N.S. PPARs and Tumor Microenvironment: The Emerging Roles of the Metabolic Master Regulators in Tumor Stromal-Epithelial Crosstalk and Carcinogenesis. Cancers 2021, 13, 2153.
  65. Gou, Q.; Che, S.; Chen, M.; Chen, H.; Shi, J.; Hou, Y. PPARγ inhibited tumor immune escape by inducing PD-L1 autophagic degradation. Cancer Sci. 2023, 114, 2871–2881.
Subjects: Oncology
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Update Date: 26 Feb 2024