The use of Cox-2 and PPARγ signaling in anti-cancer therapies (Review)

  • Authors:
    • Lucia Knopfová
    • Jan Šmarda
  • View Affiliations

  • Published online on: March 1, 2010
  • Pages:257-264
Metrics: HTML 0 views | PDF 0 views     Cited By (CrossRef): 0 citations


Increased production of the pro-inflammatory enzyme cyclooxygenase-2 (Cox-2) and altered expression and activity of peroxisome proliferator-activated receptor γ (PPARγ) have been observed in many malignancies. Both the PPARγ ligands and the Cox-2 inhibitors possess anti-inflammatory and anti-neoplastic effects in vitro and have been assessed for their therapeutic potential in several pre-clinical and clinical studies. Recently, multiple interactions between PPARγ and Cox-2 signaling pathways have been revealed. Understanding of the cross-talk between PPARγ and Cox-2 might provide important novel strategies for the effective treatment and/or prevention of cancer. This article summarizes recent achievements involving the functional interactions between the PPARγ and Cox-2 signaling pathways and discusses the implications of such interplay for clinical use.



Cox-2 and regulation of PPARγ

PPARγ ligands as Cox-2 activators

PPARγ ligands as Cox-2 suppressors

Cox-2 inhibitors and PPARγ ligands can act synergistically to suppress Cox-2 and activate PPARγ



Despite extensive research during the last decade, the role of cyclooxygenase-2 (Cox-2) and peroxisome proliferator-activated receptor γ (PPARγ) in cancerogenesis remains controversial. Therefore, potential clinical outcomes of their respective inhibitors and activators are still elusive. Nevertheless, the effects of these agents are promising enough to prompt further research of the involved cell signaling pathways. Recently, this research has revealed multiple interactions between Cox-2 and PPARγ pathways that may be important for anti-cancer therapies.

Cyclooxygenase is the rate-limiting enzyme involved in the synthesis of prostaglandins (PGs). There are two isoforms of this enzyme, the constitutive Cox-1 and the inducible one, Cox-2. cox-2 gene expression is induced by a wide variety of stimuli in cells of organisms fighting inflammatory disorders and cancer. Therefore, the level of the Cox-2 protein is elevated in various types of cancer cells in comparison with non-malignant tissues (1). A growing body of evidence suggests an association of Cox-2 with tumor development, aggressivity, resistance to standard therapy and unfavorable patient outcome. Cox-2 may participate in cancer development through multiple mechanisms, including stimulation of growth, migration, invasiveness, resistance to apoptosis and enhancement of angiogenesis (2).

In addition to a number of pre-clinical studies revealing the anti-proliferative and pro-apoptotic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and specific Cox-2 inhibitors, multiple population studies have documented that chronic intake of NSAIDs is associated with a decreased incidence of colorectal, prostate, bladder, breast and lung cancers (38). There is also clinical evidence demonstrating the reduction of colorectal polyps by the Cox-2 inhibitor celecoxib (9). Several pre-clinical and clinical studies have repeatedly demonstrated that specific Cox-2 inhibitors are promising enhancers of chemotherapy (1013).

Nevertheless, the safety of Cox-2 inhibitors in anti-cancer therapies is still a matter of debate. Although the tumor-suppressive effects of NSAIDs were attributed to their ability to act as Cox-2 inhibitors, some effects of these agents cannot be explained by inhibition of Cox-2, as these drugs can also provoke responses in Cox-2-negative cells. This suggests that there are some Cox-2-independent pathways involved in the anti-cancer effects of these agents. Therefore, inhibition of Cox-2 activity and PG synthesis is not necessarily beneficial in general; moreover, it can induce even adverse effects (14,15). Considering both the benefits and risks of Cox-2 inhibition, there is still great concern regarding the potential use of Cox-2-specific inhibitors in combination with other anti-cancer therapeutics, including the PPAR ligands.

PPARγ is a member of the nuclear hormone receptor superfamily functioning as a ligand-dependent transcription factor (16). PPAR affects gene expression either directly through binding to peroxisome proliferator response elements (PPREs) located upstream of controlled genes or indirectly by interfering with other pathways driven by transcription factors resulting in the silencing of gene transcription.

Natural ligands of PPARγ are mostly metabolites of arachidonic acid; they include polyunsaturated fatty acids, cyclopentenone prostaglandin 15-deoxy-D12,14 prostaglandin J2 (15d-PGJ2) and oxidized lipids (17,18). Synthetic ligands include the thiazolidinediones (such as troglitazone, pioglitazone and rosiglitazone) that have been clinically used in the treatment of type II diabetes (1921).

Recently, the role of PPARγ in various human cancers has been intensively studied. PPARγ expression has been reported in a variety of tumors, including colon (22), breast (23), prostate (2426), stomach (27), lung (28), pancreas (29), ovarian (30) and cervical tumors (31). Both natural and synthetic PPARγ ligands inhibit cancer cell growth in vitro and in vivo (32,33). These studies, coupled with clinical trials (34,35), suggest that PPARγ is a novel target for the development of novel and effective anti-cancer therapies.

However, there is considerable concern regarding the significance and safety of PPARγ ligands used as anti-cancer drugs (36). The mechanism of their action is still elusive, since both PPARγ-dependent and PPARγ-independent pathways mediate their anti-proliferative and pro-apoptotic effects. Furthermore, the biological significance of PPARγ is still a controversial issue. There are studies illustrating even tumor-promoting effects of PPARγ, in particular in colon and breast cancer models (3739).

Therefore, both Cox-2 and PPARγ are considered as possible targets for anti-cancer therapy and prevention, but applications of Cox-2 inhibitors as well as PPARγ ligands in therapy remain controversial. Detailed understanding of the molecular mechanisms and signaling pathways may elucidate the pros and cons of their action and provide more effective therapeutical approaches. Recent findings involving the cross-talk between Cox-2 and PPAR signaling may have such therapeutically relevant implications. This review summarizes the current knowledge on the interplay between Cox-2 and PPARγ signaling pathways and focuses on the benefits and risks of the combined application of Cox-2 inhibitors and PPARγ ligands in anti-cancer therapy.

Cox-2 and regulation of PPARγ

Several components of the Cox-2 metabolic pathway were shown to activate PPARγ (Fig. 1). The molecules serving as substrates as well as products of Cox-2 enzymatic activity include the PPARγ ligands. Various polyunsaturated fatty acids (PUFAs), such as arachidonic (AA) and eicosapentaenoic acid (EPA), once released from the membrane phospholipids by phospholipase A2 (PLA2), can either be metabolized by Cox or enter the nucleus to activate PPARγ (40,41). The ability of PUFAs to activate PPARγ may depend on expression and activity of Cox-2. The effect of EPA on the transactivation function of PPARγ is weaker in pancreatic cancer cells expressing Cox-2 than in Cox-2-negative cells, presumably due to the rapid metabolization of EPA by Cox-2. Nevertheless, the EPA-induced growth inhibition of pancreatic (40) and colon cells (42) is mediated by the activation of PPARγ.

Various Cox-2 products can also bind and activate PPARγ. Cox-2 catalyzes formation of a chemically unstable prostaglandin H2 (PGH2) which can be further converted to various prostanoids (e.g., PGE2, PGD2 and PGF2α) by tissue-specific isomerases. Dehydration of these PGs leads to the formation of cyclopentenone prostaglandins PGA2, PGA1 and PGJ2 (43). 15d-PGJ2 is formed from PGJ2 by further nonenzymatic rearrangements and dehydration. While prostaglandins PGE2, PGF2α and PGD2 transduce their signals through binding to the G-protein-coupled cell surface receptors (44), cyclopentenone prostaglandins (e.g., 15d-PGJ2) are known ligands of PPARγ.

While PGE2, which is considered to be the major Cox-2 product, possesses pro-inflammatory and tumor-promoting effects (45,46), accumulating data suggest that 15d-PGJ2 acts as an anti-inflammator (47). Therefore, both pro- and anti-inflammatory effects can be controlled by Cox-2. During the early phase of inflammation, Cox-2 expression and activity is induced and associated with increased synthesis of PGE2. During the later phase, Cox-2 may be involved in the resolution of acute inflammation by generating an alternate set of PGs, such as those of the cyclopentenone family (15). Anti-inflammatory effects of cyclopentanone PGs are mediated either by binding/activating PPARγ or by interaction with other target molecules, such as NF-κB or IκB kinase (43).

Although the anti-inflammatory effect of 15d-PGJ2 is well known and accepted, the results concerning the effects of cyclopentanone PGs on tumor growth are still conflicting. 15d-PGJ2 was found to possess anti-neoplastic properties; it inhibits cell growth, induces terminal differentiation and apoptotic cell death in a variety of tumor cells, thereby promoting phenotypic changes associated with a less malignant status (23,35,48). In contrast, there are reports demonstrating the tumor-promoting action of 15d-PGJ2 as well (49,50).

On the other hand, Cox-2 can produce metabolites inhibiting PPARγ. PGF2α, acting through its cell surface G-protein-coupled receptor, inhibits PPARγ through MAP kinase-dependent phosphorylation. The antagonistic effects of PGJ2 and PGF2α on the activity of PPARγ result in opposing effects of these compounds on adipocyte differentiation. PGJ2 stimulates, while PGF2α blocks, adipogenesis (51). Similarly, antagonistic effects of 15d-PGJ2 and PGF2α were observed in B lymphoma cells; 15d-PGJ2 induced apoptosis via PPARγ activation, while PGF2α pretreatment attenuated its cytotoxic effect (52).

Moreover, not only the Cox-2 substrates and products can be PPAR ligands, PPARγ activity can also be stimulated by Cox-2 inhibitors. Ibuprofen, indomethacin and some other NSAIDs can both inhibit Cox-1/Cox-2 and function as PPARγ ligands in various cell systems as well (53,54). Celecoxib, a selective Cox-2 inhibitor, binds and activates PPARγ in rat mesangial cells (55). NS-398, another selective inhibitor of Cox-2, has been found to increase expression of PPARγ, PPARα and PPARβ in human fibroblasts (56). PPARγ expression was up-regulated in lung tumors in mice treated with nimesulfide, another Cox-2-specific inhibitor, when compared to tumor tissue of untreated mice (57). Indomethacin and other NSAIDs as well as NS-398 induced growth suppression and apoptosis associated with activation of PPARγ in rheumatoid synovial cells. 15d-PGJ2 and troglitazone, other PPARγ ligands have a similar inhibitory effect on the growth of synovial cells (58). Mechanisms of celecoxib-induced inhibition of hepatocellular carcinoma cell growth involve up-regulation of PPARγ (59). Therefore, activation of PPARγ is considered as one of the Cox-2-independent mechanisms responsible for the anti-inflammatory and anti-neoplastic effects of NSAIDs. Induction of PPARγ can account for the puzzling fact that selective Cox-2 inhibitors display anti-proliferative properties in cells lacking Cox-2 expression. It has been demonstrated that JTE-522, a Cox-2-specific inhibitor, interferes with the growth of Cox-2-negative HCC cells. This growth arrest is, in part, mediated by up-regulation of PPARγ protein expression (60). We conclude that PPARγ activity can be induced by several Cox-2 inhibitors and possibly participates in mediating the effects that cannot be attributed to the Cox-2 inhibition itself.

PPARγ ligands as Cox-2 activators

There are numerous studies documenting PPARγ ligand-induced Cox-2 up-regulation. Endogenous PPARγ ligand 15d-PGJ2, as well as synthetic PPARγ agonists, stimulate cox-2 expression and activity in several cell types (49,6166). However, the mechanism of this up-regulation varies significantly in different cell types and according to the specificity of the activating stimulus. cox-2 transcription can be directly activated by PPARγ itself, and the peroxisome proliferator responsive element (PPRE) was indentified in the cox-2 promoter sequence (61). The artificial construct containing the cox-2 promoter including PPRE was activated in cells cotransfected with vectors encoding PPARα, δ and γ. Similarly, PPRE in the cox-2 promoter was required for the PPARγ ligand rosiglitazone-induced activation of the reporter (62,67). PPARγ-dependent activation of Cox-2 by rosiglitazone was observed in smooth muscle cells, and it was sensitive to the PPARγ antagonist (63).

Notably, several Cox-2 inhibitors (such as ibuprofen, sulindac sulfide, NS-398 and mefenamic acid) while inhibiting Cox-2 activity, also enhance its expression, possibly by binding and activating PPARγ (61). It was demonstrated that indomethacin and naproxen stimulate cox-2 expression at concentrations that were shown to activate PPARγ (64). Detailed study of the mechanism of indomethacin-, flurbiprofen- and NS-398-induced Cox-2 expression was performed by Pang et al (68). They found that NSAIDs as well as 15d-PGJ2 induced the transcriptional activity of the Cox-2-reporter construct containing the PPRE, but had no effect on the Cox-2-reporter construct lacking the PPRE. These results revealed that stimulation of cox-2 expression by NSAIDs involves PPARγ activation and provide the first direct evidence that the PPRE in the promoter is required for NSAID-induced Cox-2 expression.

On the other hand, there are multiple studies suggesting that Cox-2 activation induced by some PPARγ ligands is PPARγ-independent. In human synovial fibroblasts treated with both natural and synthetic PPAR ligands, Cox-2 mRNA and protein synthesis were up-regulated in a dose-dependent manner. It is interesting to note that synthetic ligands WY-14,643 and ciglitazone induce Cox-2 expression via PPAR/PPRE-dependent, promoter-based transcriptional activation, but 15d-PGJ2 probably does so by a PPAR-independent mechanism (64). Results obtained by Lee et al (65) in articular chondrocytes are in agreement with this observation; PPARγ antagonists do not block 15d-PGJ2-induced Cox-2 expression. However, not only 15d-PGJ2, but even synthetic PPARγ ligands perform PPAR-independent cox-2 induction. Troglitazone-induced Cox-2 expression in human lung epithelial A549 cells was not mediated via PPARγ but via activation of the ERK and PI3K pathways instead (66). Another signaling transducer involved in cox-2 up-regulation by PPARγ ligands is MAPK p38. Both 15d-PGJ2 and synthetic PPARγ ligand GW7845 induced Cox-2 synthesis in the MC615 cartilage cell line. Pretreatment of the cells with the p38-specific inhibitor repressed expression of Cox-2 induced by both 15d-PGJ2 and GW7845 (69). In neuronal cells, p38 was also involved in Cox-2 induction by 15d-PGJ2, and again an involvement of PPARγ was excluded (70). These findings correspond with the fact, that p38 is an activator of NF-κB during inflammation and cox-2 belongs among theNF-κB-regulated genes (71,72). This suggests a possible signaling pathway leading to Cox-2 up-regulation by 15d-PGJ2 without PPARγ participation.

In conclusion, both natural and synthetic PPARγ ligands are able to activate cox-2 expression either by PPARγ-dependent or -independent mechanisms, and the latter might be mediated via activation of the MAPK pathway (Fig. 2A).

PPARγ ligands as Cox-2 suppressors

There are also studies reporting that PPARγ ligands have two opposing effects on cox-2 expression. Although NSAIDs can increase the basal Cox-2 level, they inhibit cytokine-induced cox-2 expression. For example, flufenamic acid inhibits lipopolysaccharide (LPS)- and tumor necrosis factor α (TNFα)-induced cox-2 expression in RAW 264.7 and HT-29 cells, whereas it induces cox-2 expression in the absence of LPS or TNFα. However, the inhibitory effect of NSAIDs on cytokine-induced cox-2 expression is mediated rather via NF-κB inhibition than PPARγ activation, while NSAID-induced cox-2 expression is mediated through signaling pathways that do not require the activation of MAPKs and NF-κB, but might involve activation of PPARγ (73). Not only NSAIDs but also endogenous PPARγ ligand 15d-PGJ2 inhibits IL-β-induced Cox-2 up-regulation. Also in this case, Cox-2 down-regulation is mediated by NF-κB inhibiton but not by PPARγ activation (74).

However, in cells with overexpressed and constitutively active Cox-2, some PPARγ activators can inhibit cox-2 expression as well (75,76). It is notable that some studies proved PPARγ involvement in Cox-2 down-regulation (77), while others described Cox-2 down-regulation as a PPARγ-independent phenomenon (76). Hazra and Dubinett (76) used dominant negative PPARγ to show that ciglitazone decreases cox-2 promoter activity in a PPARγ-independent manner. On the other hand, Bren-Mattison et al (77) showed that PPARγ overexpression suppresses cox-2 transcription. This discrepancy is explained by the fact that Cox-2 is not down-regulated due to PPARγ trans-repressing effect but due to the inhibition of some other transcription factors such as NF-κB or C/EBP. The cox-2 gene is under the control of NF-κB and is negatively regulated by various PPARγ ligands via either PPARγ-dependent or -independent repression of NF-κB (17). PPARγ can inhibit NF-κB by stimulation of IκB transcription (78). PPARγ-induced IκB synthesis accounts for at least some of the anti-inflammatory effects of PPARγ ligands (7981). 15d-PGJ2 can inhibit NF-κB independently of PPARγ as well, either by inhibiting the IκB kinase, therefore preventing IκB phosphorylation and degradation (82,83), or directly by interacting with NF-κB (84).

In conclusion, 15d-PGJ and some synthetic PPARγ ligands can down-regulate the cytokine-stimulated and in some cases unstimulated cox-2 expression through inhibition of NF-κB or other transcription factors which can occur either via PPARγ-dependent or PPARγ-indepedent mechanisms (Fig. 2B).

Cox-2 inhibitors and PPARγ ligands can act synergistically to suppress Cox-2 and activate PPARγ

Despite the facts disclosed in the previous sections documenting the complex and somewhat ambivalent interplay between Cox-2 and PPARγ pathways, several studies indicate a possible coordinated effects of Cox-2 inhibitors and PPARγ activators and suggest the combined treatment as a promising therapeutic strategy.

Simultaneous targeting of Cox-2 and PPARγ was found to result in the synergistic inhibition of mammary cancer development (85). Treatment of MDA-MB-231 breast cancer cells with NS-398 (a Cox-2 inhibitor) or ciglitazone (a PPARγ ligand) inhibited cell proliferation and markedly increased rates of apoptosis. Compared to using both agents separately, combined treatment resulted in the synergistic inhibition of cell proliferation and induction of apoptosis. Thus, the combinatorial targeting of Cox-2 and PPARγ possesses a stronger anti-neoplastic effect in vitro than targeting each molecule separately (86). This result was confirmed with a different combination of the Cox-2 inhibitor (celecoxib) and PPARγ agonist (F-L-Leu) in animal breast cancer models (87,88). Celecoxib and F-L-Leu cooperated in the growth inhibition of a mouse mammary adenocarcinoma cell (MMAC-1) line in vitro. In mice the combined diet of celecoxib and F-L-Leu delayed the median age of death due to mammary tumors more effectively than celecoxib alone (88).

Breast cancer is not the only possible candidate for combinatorial therapy with Cox-2 inhibitors and PPARγ ligands, as the combination of NS-398 and rosiglitazone exerted synergistic effects in the inhibition of proliferation and induction of apoptosis of human pancreatic carcinoma cells as well (89). Narayanan et al (90) showed that low doses of celecoxib in combination with DHA which functions as a PPAR ligand in prostate cancer cells could be a highly promising strategy for prostate cancer chemoprevention while minimizing undesired side effects. Combined treatment with DHA and celecoxib increased PPARγ expression and activity, decreased the Cox-2 level, inhibited cell growth and induced apoptosis more efficiently than each agent alone.

Badawi et al (87) examined the effect of a combination of celecoxib and F-L-Leu on the development of methylnitrosourea (MNU)-induced rat mammary gland carcinogenesis. They found that celecoxib and F-L-Leu significantly reduced tumor incidence and multiplicity in a synergistic manner. The molecular mechanism underlying the anti-cancer effect of these agents is partially based on Cox-2 down- and PPARγ up-regulation. Both celecoxib and F-L-Leu separately inhibit the production of Cox-2 and PGE2 and up-regulate expression of PPARγ. Combined treatment further potentiates these effects.


There is cross-talk between the Cox-2- and PPARγ-driven pathways. An inverse correlation between Cox-2 and PPARγ expression/activity was demostrated to occur in various types of human cancers, and it significantly affects carcinogenesis (22,23,91,92); the weaker the expression of PPARγ, the higher the level of Cox-2/PGE2 and the more tumor development progresses (23,93). Inhibition of Cox-2 and activation of PPARγ prevent cancer growth in vitro and in vivo. There is now strong evidence documenting that both Cox-2 inhibitors and PPARγ agonists exert their anti-tumor effects not only via their respective targets, Cox-2 and PPARγ. Various Cox-2-independent anti-inflammatory and anti-neoplastic effects of NSAIDs can be mediated via PPARγ activation (60), and Cox-2 suppression might be responsible for the anti-cancer effects of PPARγ ligands (77). Combined treatment with both classes of agents can exert an additive, if not synergistic, inhibition in human cancer (87). However, the interplay between these systems is very complex. Several components of the Cox-2 metabolic pathway regulate PPARγ activity, and PPARγ ligands modulate cox-2 expression, both positively and negatively, both in PPARγ-dependent and PPARγ-independent manners. Although several studies have demonstrated the synergistic anti-cancer effects of PPARγ ligands in combination with Cox-2 inhibitors, particularly in breast cancer models, further pre-clinical and clinical trials are required to clarify the role that simultaneous Cox-2 inhibition and PPARγ activation may play in the treatment of human cancer.


We thank Filip Trčka for drawing the schemes. This work was supported by grants no. 301/09/1115 and 204/08/H054 of the Czech Science Foundation, MSM0021622415 of the Ministry of Education, Youth and Sports of the Czech Republic and MUNI/0099/2009 of Masaryk University.



Zha S, Yegnasubramanian V, Nelson WG, Isaacs WB and De Marzo AM: Cyclooxygenases in cancer: progress and perspective. Cancer Lett. 215:1–20. 2004. View Article : Google Scholar : PubMed/NCBI


Liao Z, Mason KA and Milas L: Cyclo-oxygenase-2 and its inhibition in cancer: is there a role? Drugs. 67:821–845. 2007. View Article : Google Scholar : PubMed/NCBI


Koehne CH and Dubois RN: COX-2 inhibition and colorectal cancer. Semin Oncol. 31:12–21. 2004. View Article : Google Scholar


Khuder SA and Mutgi AB: Breast cancer and NSAID use: a meta-analysis. Br J Cancer. 84:1188–1192. 2001. View Article : Google Scholar : PubMed/NCBI


Castelao JE, Yuan JM, Gago-Dominguez M, Yu MC and Ross RK: Non-steroidal anti-inflammatory drugs and bladder cancer prevention. Br J Cancer. 82:1364–1369. 2000.PubMed/NCBI


Sooriakumaran P, Langley SE, Laing RW and Coley HM: COX-2 inhibition: a possible role in the management of prostate cancer? J Chemother. 19:21–32. 2007. View Article : Google Scholar : PubMed/NCBI


Muscat JE, Chen SQ, Richie JP Jr, Altorki NK, Citron M, Olson S, Neugut AI and Stellman SD: Risk of lung carcinoma among users of nonsteroidal antiinflammatory drugs. Cancer. 97:1732–1736. 2003. View Article : Google Scholar : PubMed/NCBI


Sandler AB and Dubinett SM: COX-2 inhibition and lung cancer. Semin Oncol. 31:45–52. 2004. View Article : Google Scholar : PubMed/NCBI


Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK and Levin B: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 342:1946–1952. 2000. View Article : Google Scholar : PubMed/NCBI


Suzuki R, Yamamoto M, Saka H, Taniguchi H, Shindoh J, Tanikawa Y, Nomura F, Gonda H, Imaizumi K, Hasegawa Y and Shimokata K: A phase II study of carboplatin and paclitacel with meloxicam. Lung Cancer. 63:72–76. 2009. View Article : Google Scholar : PubMed/NCBI


Soriano F, Helfrich B, Chan DC, Heasley LE, Bunn PA Jr and Chou TC: Synergistic effects of new chemopreventive agents and conventional cytotoxic agents against human lung cancer cell lines. Cancer Res. 59:6178–6184. 1999.PubMed/NCBI


Tuettenberg J, Grobholz R, Korn T, Wenz F, Erber R and Vajkoczy P: Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme. J Cancer Res Clin Oncol. 131:31–40. 2005. View Article : Google Scholar : PubMed/NCBI


Tachimori A, Yamada N, Amano R, Ohira M and Hirakawa K: Combination therapy of S-1 with selective cyclooxygenase-2 inhibitor for liver metastasis of colorectal carcinoma. Anticancer Res. 28:629–638. 2008.PubMed/NCBI


Eichele K, Ramer R and Hinz B: Decisive role of cyclooxygenase-2 and lipocalin-type prostaglandin D synthase in chemotherapeutic-induced apoptosis of human cervical carcinoma cells. Oncogene. 27:3032–3044. 2008. View Article : Google Scholar : PubMed/NCBI


Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ and Willoughby DA: Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med. 5:698–701. 1999. View Article : Google Scholar : PubMed/NCBI


Issemann I and Green S: Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 347:645–650. 1990. View Article : Google Scholar : PubMed/NCBI


Nosjean O and Boutin JA: Natural ligands of PPARγ: Are prostaglandin J2 derivatives really playing the part? Cell Signal. 14:573–583. 2002.


Bull AW, Steffensen KR, Leers J and Rafter JJ: Activation of PPAR gamma in colon tumor cell lines by oxidized metabolites of linoleic acid, endogenous ligands for PPAR gamma. Carcinogenesis. 24:1717–1722. 2003. View Article : Google Scholar : PubMed/NCBI


Kepez A, Oto A and Dagdelen S: Peroxisome proliferator-activated receptor-gamma: novel therapeutic target linking adiposity, insulin resistance and atherosclerosis. BioDrugs. 20:121–135. 2006.


Chiarelli F and Di Marzio D: Peroxisome proliferator-activated receptor-gamma agonists and diabetes: current evidence and future perspectives. Vasc Health Risk Manag. 4:297–304. 2008.PubMed/NCBI


Quinn CE, Hamilton PK, Lockhart CJ and McVeigh GE: Thiazolidinediones: effects on insulin resistance and the cardiovascular system. Br J Pharmacol. 153:636–645. 2008. View Article : Google Scholar : PubMed/NCBI


Konstantinopoulos PA, Vandoros GP, Sotiropoulou-Bonikou G, Kominea A and Papavassiliou AG: NF-κB/PPARγ and/or AP-1/PPARγ ‘on/off’ switches and induction of CBP in colon adenocarcinomas: correlation with COX-2 expression. Int J Colorectal Dis. 22:57–68. 2007.


Badawi AF and Badr MZ: Expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor-gamma and levels of prostaglandin E2 and 15-deoxy-delta12,14-prostaglandin J2 in human breast cancer and metastasis. Int J Cancer. 103:84–90. 2003. View Article : Google Scholar


Nagata D, Yoshihiro H, Nakanishi M, Naruyama H, Okada S, Ando R, Tozawa K and Kohri K: Peroxisome proliferator-activated receptor-gamma and growth inhibition by its ligands in prostate cancer. Cancer Detect Prev. 32:259–266. 2008. View Article : Google Scholar : PubMed/NCBI


Matsuyama M and Yoshimura R: Peroxisome proliferator-activated receptor-gamma is a potent target for prevention and treatment in human prostate and testicular cancer. PPAR Res. 2008:2498492008. View Article : Google Scholar : PubMed/NCBI


Segawa Y, Yoshimura R, Hase T, Nakatani T, Wada S, Kawahito Y, Kishimoto T and Sano H: Expression of peroxisome proliferator-activated receptor (PPAR) in human prostate cancer. Prostate. 51:108–116. 2002. View Article : Google Scholar : PubMed/NCBI


Sato H, Ishihara S, Kawashima K, Moriyama N, Suetsugu H, Kazumori H, Okuyama T, Rumi MA, Fukuda R, Nagasue N and Kinoshita Y: Expression of peroxisome proliferator-activated receptor (PPAR)gamma in gastric cancer and inhibitory effects of PPARgamma agonists. Br J Cancer. 83:1394–1400. 2000. View Article : Google Scholar : PubMed/NCBI


Inoue K, Kawahito Y, Tsubouchi Y, Yamada R, Kohno M, Hosokawa Y, Katoh D, Bishop-Bailey D, Hla T and Sano H: Expression of peroxisome proliferator-activated receptor (PPAR)-gamma in human lung cancer. Anticancer Res. 21:2471–2476. 2001.PubMed/NCBI


Kristiansen G, Jacob J, Buckendahl AC, Grützmann R, Alldinger I, Sipos B, Klöppel G, Bahra M, Langrehr JM, Neuhaus P, Dietel M and Pilarsky C: Peroxisome proliferator-activated receptor gamma is highly expressed in pancreatic cancer and is associated with shorter overall survival times. Clin Cancer Res. 12:6444–6451. 2006. View Article : Google Scholar


Vignati S, Albertini V, Rinaldi A, Kwee I, Riva C, Oldrini R, Capella C, Bertoni F, Carbone GM and Catapano CV: Cellular and molecular consequences of peroxisome proliferator-activated receptor-gamma activation in ovarian cancer cells. Neoplasia. 8:851–861. 2006. View Article : Google Scholar : PubMed/NCBI


Jung TI, Baek WK, Suh SI, Jang BC, Song DK, Bae JH, Kwon KY, Bae JH, Cha SD, Bae I and Cho CH: Down-regulation of peroxisome proliferator-activated receptor gamma in human cervical carcinoma. Gynecol Oncol. 97:365–373. 2005. View Article : Google Scholar : PubMed/NCBI


Grommes C, Landreth GE and Heneka MT: Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol. 5:419–429. 2004. View Article : Google Scholar : PubMed/NCBI


Keshamouni VG, Reddy RC, Arenberg DA, Joel B, Thannickal VJ, Kalemkerian GP and Standiford TJ: Peroxisome proliferator-activated receptor-gamma activation inhibits tumor progression in non-small-cell lung cancer. Oncogene. 23:100–108. 2004. View Article : Google Scholar : PubMed/NCBI


Yasui Y, Kim M and Tanaka T: PPAR ligands for cancer chemoprevention. PPAR Res. 2008:5489192008. View Article : Google Scholar : PubMed/NCBI


Mueller E, Smith M, Sarraf P, Kroll T, Aiyer A, Kaufman DS, Oh W, Demetri G, Figg WD, Zhou XP, Eng C, Spiegelman BM and Kantoff PW: Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci USA. 97:10990–10995. 2000. View Article : Google Scholar : PubMed/NCBI


Rumi MA, Ishihara S, Kazumori H, Kadowaki Y and Kinoshita Y: Can PPAR gamma ligands be used in cancer therapy? Curr Med Chem Anticancer Agents. 4:465–477. 2004. View Article : Google Scholar : PubMed/NCBI


Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, Briggs M, Heyman R and Auwerx J: Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med. 4:1053–1057. 1998.PubMed/NCBI


Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, Thomazy VA and Evans RM: Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med. 4:1058–1061. 1998. View Article : Google Scholar : PubMed/NCBI


Saez E, Rosenfeld J, Livolsi A, Olson P, Lombardo E, Nelson M, Banayo E, Cardiff RD, Izpisua-Belmonte JC and Evans RM: PPAR gamma signaling exacerbates mammary gland tumor development. Genes Dev. 18:528–540. 2004. View Article : Google Scholar : PubMed/NCBI


Eibl G: The role of PPAR-gamma and its interaction with COX-2 in pancreatic cancer. PPAR Res. 2008:3269152008. View Article : Google Scholar : PubMed/NCBI


Kawashima A, Harada T, Imada K, Yano T and Mizuguchi K: Eicosapentaenoic acid inhibits interleukin-6 production in interleukin-1beta-stimulated C6 glioma cells through peroxisome proliferator-activated receptor-gamma. Prostaglandins Leukot Essent Fatty Acids. 79:59–65. 2008. View Article : Google Scholar


Allred CD, Talbert DR, Southard RC, Wang X and Kilgore MW: PPARgamma1 as a molecular target of eicosapentaenoic acid in human colon cancer (HT-29) cells. J Nutr. 138:250–256. 2008.PubMed/NCBI


Straus DS and Glass CK: Cyclopentenone prostaglandins: new insights on biological activities and cellular targets. Med Res Rev. 21:185–210. 2001. View Article : Google Scholar : PubMed/NCBI


Matsuoka T and Narumiya S: Prostaglandin receptor signaling in disease. ScientificWorldJournal. 7:1329–1347. 2007. View Article : Google Scholar


Castellone MD, Teramoto H, Williams BO, Druey KM and Gutkind JS: Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science. 310:1504–1510. 2005. View Article : Google Scholar : PubMed/NCBI


Chan TA: Prostaglandins and the colon cancer connection. Trends Mol Med. 12:240–244. 2006. View Article : Google Scholar : PubMed/NCBI


Scher JU and Pillinger MH: 15d-PGJ2: the anti-inflammatory prostaglandin? Clin Immunol. 114:100–109. 2005. View Article : Google Scholar : PubMed/NCBI


Shimada T, Kojima K, Yoshiura K, Hiraishi H and Terano A: Characteristics of the peroxisome proliferator activated receptor gamma (PPARgamma) ligand-induced apoptosis in colon cancer cells. Gut. 50:658–664. 2002. View Article : Google Scholar


Millan O, Rico D, Peinado H, Zarich N, Stamatakis K, Pérez-Sala D, Rojas JM, Cano A and Boscá L: Potentiation of tumor formation by topical administration of 15-deoxy-delta12,14-prostaglandin J2 in a model of skin carcinogenesis. Carcinogenesis. 27:328–336. 2006. View Article : Google Scholar : PubMed/NCBI


Chinery R, Coffey RJ, Graves-Deal R, Kirkland SC, Sanchez SC, Zackert WE, Oates JA and Morrow JD: Prostaglandin J2 and 15-deoxy-delta12,14-prostaglandin J2 induce proliferation of cyclooxygenase-depleted colorectal cancer cells. Cancer Res. 59:2739–2746. 1999.PubMed/NCBI


Reginato MJ, Krakow SL, Bailey ST and Lazar MA: Prostaglandins promote and block adipogenesis through opposing effects on peroxisome proliferator-activated receptor gamma. J Biol Chem. 273:1855–1858. 1998. View Article : Google Scholar


Padilla J, Kaur K, Cao HJ, Smith TJ and Phipps RP: Peroxisome proliferator activator receptor-gamma agonists and 15-deoxy-delta(12,14)(12,14)-PGJ(2) induce apoptosis in normal and malignant B-lineage cells. J Immunol. 165:6941–6948. 2000. View Article : Google Scholar : PubMed/NCBI


Jaradat MS, Wongsud B, Phornchirasilp S, Rangwala SM, Shams G, Sutton M, Romstedt KJ, Noonan DJ and Feller DR: Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen and indomethacin. Biochem Pharmacol. 62:1587–1595. 2001. View Article : Google Scholar : PubMed/NCBI


Lehmann JM, Lenhard JM, Oliver BB, Ringold GM and Kliewer SA: Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 272:3406–3410. 1997. View Article : Google Scholar


López-Parra M, Clària J, Titos E, Planagumà A, Párrizas M, Masferrer JL, Jiménez W, Arroyo V, Rivera F and Rodés J: The selective cyclooxygenase-2 inhibitor celecoxib modulates the formation of vasoconstrictor eicosanoids and activates PPARgamma. Influence of albumin. J Hepatol. 42:75–81. 2005.PubMed/NCBI


Diamond MP and Saed G: Modulation of the expression of peroxisome proliferator-activated receptors in human fibroblasts. Fertil Steril. 87:706–709. 2007. View Article : Google Scholar : PubMed/NCBI


Shaik MS, Chatterjee A and Singh M: Effect of a selective cyclooxygenase-2 inhibitor, nimesulide, on the growth of lung tumors and their expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor-gamma. Clin Cancer Res. 10:1521–1529. 2004. View Article : Google Scholar


Yamazaki R, Kusunoki N, Matsuzaki T, Hashimoto S and Kawai S: Nonsteroidal anti-inflammatory drugs induce apoptosis in association with activation of peroxisome proliferator-activated receptor gamma in rheumatoid synovial cells. J Pharmacol Exp Ther. 302:18–25. 2002. View Article : Google Scholar


Cui W, Yu CH and Hu KQ: In vitro and in vivo effects and mechanisms of celecoxib-induced growth inhibition of human hepatocellular carcinoma cells. Clin Cancer Res. 11:8213–8221. 2005. View Article : Google Scholar : PubMed/NCBI


Nagahara T, Okano J and Murawaki Y: Mechanisms of anti-proliferative effect of JTE-522, a selective cyclooxygenase-2 inhibitor, on human liver cancer cells. Oncol Rep. 18:1281–1290. 2007.PubMed/NCBI


Meade EA, McIntyre TM, Zimmerman GA and Prescott SM: Peroxisome proliferators enhance cyclooxygenase-2 expression in epithelial cells. J Biol Chem. 274:8328–8334. 1999. View Article : Google Scholar : PubMed/NCBI


Pontsler AV, St Hilaire A, Marathe GK, Zimmerman GA and McIntyre TM: Cyclooxygenase-2 is induced in monocytes by peroxisome proliferator activated receptor gamma and oxidized alkyl phospholipids from oxidized low density lipoprotein. J Biol Chem. 277:13029–13036. 2002. View Article : Google Scholar : PubMed/NCBI


Bishop-Bailey D and Warner TD: PPARgamma ligands induce prostaglandin production in vascular smooth muscle cells: indomethacin acts as a peroxisome proliferator-activated receptor-gamma antagonist. FASEB J. 17:1925–1927. 2003.


Kalajdzic T, Faour WH, He QW, Fahmi H, Martel-Pelletier J, Pelletier JP and Di Battista JA: Nimesulide, a preferential cyclooxygenase 2 inhibitor, suppresses peroxisome proliferator-activated receptor induction of cyclooxygenase 2 gene expression in human synovial fibroblasts: evidence for receptor antagonism. Arthritis Rheum. 46:494–506. 2002. View Article : Google Scholar


Lee JH, Yu SM, Yoon EK, Lee WK, Jung JC and Kim SJ: 15-Deoxy-delta 12,14-prostaglandin J2 regulates dedifferentiation through peroxisome proliferator-activated receptor-gamma-dependent pathway but not COX-2 expression in articular chondrocytes. J Korean Med Sci. 22:891–897. 2007. View Article : Google Scholar


Patel KM, Wright KL, Whittaker P, Chakravarty P, Watson ML and Ward SG: Differential modulation of COX-2 expression in A549 airway epithelial cells by structurally distinct PPAR(gamma) agonists: evidence for disparate functional effects which are independent of NF-(kappa)B and PPAR(gamma). Cell Signal. 17:1098–1110. 2005. View Article : Google Scholar


Chêne G, Dubourdeau M, Balard P, Escoubet-Lozach L, Orfila C, Berry A, Bernad J, Aries MF, Charveron M and Pipy B: n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells. Biochim Biophys Acta. 1771:576–589. 2007.PubMed/NCBI


Pang L, Nie M, Corbett L and Knox AJ: Cyclooxygenase-2 expression by nonsteroidal anti-inflammatory drugs in human airway smooth muscle cells: role of peroxisome proliferator-activated receptors. J Immunol. 170:1043–1051. 2003. View Article : Google Scholar : PubMed/NCBI


Ulivi V, Cancedda R and Cancedda FD: 15-Deoxy-delta 12,14-prostaglandin J(2) inhibits the synthesis of the acute phase protein SIP24 in cartilage: involvement of COX-2 in resolution of inflammation. J Cell Physiol. 217:433–441. 2008. View Article : Google Scholar : PubMed/NCBI


Li Z, Jansen M, Ogburn K, Salvatierra L, Hunter L, Mathew S and Figueiredo-Pereira ME: Neurotoxic prostaglandin J2 enhances cyclooxygenase-2 expression in neuronal cells through the p38MAPK pathway: a death wish? J Neurosci Res. 78:824–836. 2004. View Article : Google Scholar : PubMed/NCBI


Ulivi V, Giannoni P, Gentili C, Cancedda R and Descalzi F: p38/NF-κB-dependent expression of COX-2 during differentiation and inflammatory response of chondrocytes. J Cell Biochem. 104:1393–1406. 2008.PubMed/NCBI


Tsatsanis C, Androulidaki A, Venihaki M and Margioris AN: Signalling networks regulating cyclooxygenase-2. Int J Biochem Cell Biol. 38:1654–1661. 2006. View Article : Google Scholar : PubMed/NCBI


Paik JH, Ju JH, Lee JY, Boudreau MD and Hwang DH: Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase. Mediation through different signaling pathways. J Biol Chem. 275:28173–28179. 2000.


Boyault S, Simonin MA, Bianchi A, Compe E, Liagre B, Mainard D, Becuwe P, Dauca M, Netter P, Terlain B and Bordji K: 15-Deoxy-Δ12;14-PGJ2, but not troglitazone, modulates IL-1β effects in human chondrocytes by inhibiting NF-κB and AP-1 activation pathways. FEBS Lett. 501:24–30. 2001.


Liu JJ, Liu PQ, Lin DJ, Xiao RZ, Huang M, Li XD, He Y and Huang RW: Downregulation of cyclooxygenase-2 expression and activation of caspase-3 are involved in peroxisome proliferator-activated receptor-gamma agonists induced apoptosis in human monocyte leukemia cells in vitro. Ann Hematol. 86:173–183. 2007. View Article : Google Scholar


Hazra S and Dubinett SM: Ciglitazone mediates COX-2 dependent suppression of PGE2 in human non-small cell lung cancer cells. Prostaglandins Leukot Essent Fatty Acids. 77:51–58. 2007. View Article : Google Scholar : PubMed/NCBI


Bren-Mattison Y, Meyer AM, van Putten V, Li H, Kuhn K, Stearman R, Weiser-Evans M, Winn RA, Heasley LE and Nemenoff RA: Antitumorigenic effects of peroxisome proliferator-activated receptor-gamma in non-small cell lung cancer cells are mediated by suppression of cyclooxygenase-2 via inhibition of nuclear factor-kappaB. Mol Pharmacol. 73:709–717. 2008. View Article : Google Scholar


Delerive P, Gervois P, Fruchart JC and Staels B: Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem. 275:36703–36707. 2000. View Article : Google Scholar


Moraes LA, Piqueras L and Bishop-Bailey D: Peroxisome proliferator-activated receptors and inflammation. Pharmacol Ther. 110:371–385. 2006. View Article : Google Scholar


Wahli W: A gut feeling of the PXR, PPAR and NF-κB connection. J Intern Med. 263:613–619. 2008.PubMed/NCBI


Ricote M, Li AC, Willson TM, Kelly CJ and Glass CK: The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature. 391:79–82. 1998.


Rossi A, Kapahi P, Natoli G, Takahashi T, Chen Y, Karin M and Santoro MG: Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature. 403:103–108. 2000. View Article : Google Scholar : PubMed/NCBI


Ackerman WE, Zhang XL, Rovin BH and Kniss DA: Modulation of cytokine-induced cyclooxygenase 2 expression by PPARG ligands through NFκB signal disruption in human WISH and amnion cells. Biol Reprod. 73:527–535. 2005.PubMed/NCBI


Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH, Sengchanthalangsy LL, Ghosh G and Glass CK: 15-Deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway. Proc Natl Acad Sci USA. 97:4844–4849. 2000.


Badawi AF and Badr MZ: Chemoprevention of breast cancer by targeting cyclooxygenase-2 and peroxisome proliferator-activated receptor-γ. Int J Oncol. 20:1109–1122. 2002.


Michael MS, Badr MZ and Badawi AF: Inhibition of cyclooxygenase-2 and activation of peroxisome proliferator-activated receptor-γ synergistically induces apoptosis and inhibits growth of human breast cancer cells. Int J Mol Med. 11:733–736. 2003.


Badawi AF, Eldeen MB, Liu Y, Ross EA and Badr MZ: Inhibition of rat mammary gland carcinogenesis by simultaneous targeting of cyclooxygenase-2 and peroxisome proliferator-activated receptor gamma. Cancer Res. 64:1181–1189. 2004. View Article : Google Scholar : PubMed/NCBI


Mustafa A and Kruger WD: Suppression of tumor formation by a cyclooxygenase-2 inhibitor and a peroxisome proliferator-activated receptor gamma agonist in an in vivo mouse model of spontaneous breast cancer. Clin Cancer Res. 14:4935–4942. 2008. View Article : Google Scholar


Sun WH, Chen GS, Ou XL, Yang Y, Luo C, Zhang Y, Shao Y, Xu HC, Xiao B, Xue YP, Zhou SM, Zhao QS and Ding GX: Inhibition of COX-2 and activation of peroxisome proliferator-activated receptor gamma synergistically inhibits proliferation and induces apoptosis of human pancreatic carcinoma cells. Cancer Lett. 275:247–255. 2009. View Article : Google Scholar


Narayanan NK, Narayanan BA and Reddy BS: A combination of docosahexaenoic acid and celecoxib prevents prostate cancer cell growth in vitro and is associated with modulation of nuclear factor-κB, and steroid hormone receptors. Int J Oncol. 26:785–792. 2005.PubMed/NCBI


Gustafsson A, Hansson E, Kressner U, Nordgren S, Andersson M, Wang W, Lönnroth C and Lundholm K: EP1-4 subtype, COX and PPAR gamma receptor expression in colorectal cancer in prediction of disease-specific mortality. Int J Cancer. 121:232–240. 2007. View Article : Google Scholar : PubMed/NCBI


Hazra S, Peebles KA, Sharma S, Mao JT and Dubinett SM: The role of PPARgamma in the cyclooxygenase pathway in lung cancer. PPAR Res. 2008:7905682008. View Article : Google Scholar : PubMed/NCBI


Sasaki H, Tanahashi M, Yukiue H, Moiriyama S, Kobayashi Y, Nakashima Y, Kaji M, Kiriyama M, Fukai I, Yamakawa Y and Fujii Y: Decreased peroxisome proliferator-activated receptor gamma gene expression was correlated with poor prognosis in patients with lung cancer. Lung Cancer. 36:71–76. 2002. View Article : Google Scholar

Related Articles

Journal Cover

March 2010
Volume 1 Issue 2

Print ISSN: 1792-0981
Online ISSN:1792-1015

2016 Impact Factor: 1.261
Ranked #50/128 Medicine Research and Experimental
(total number of cites)

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
Knopfová, L., & Knopfová, L. (2010). The use of Cox-2 and PPARγ signaling in anti-cancer therapies (Review) . Experimental and Therapeutic Medicine, 1, 257-264.
Knopfová, L., Šmarda, J."The use of Cox-2 and PPARγ signaling in anti-cancer therapies (Review) ". Experimental and Therapeutic Medicine 1.2 (2010): 257-264.
Knopfová, L., Šmarda, J."The use of Cox-2 and PPARγ signaling in anti-cancer therapies (Review) ". Experimental and Therapeutic Medicine 1, no. 2 (2010): 257-264.