Both PPARγ and PPARδ influence sulindac sulfide-mediated p21WAF1/CIP1 upregulation in a human prostate epithelial cell line

Jarvis, Morag C; Gray, Tim J.B.; Palmer, Colin N.A.

doi:10.1038/sj.onc.1208983

Cited by 28 publications

(27 citation statements)

References 18 publications

(17 reference statements)

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“…It has recently been reported that up-regulation of p21, with associated growth suppression, following sulindac treatment may be mediated in part through activation of the nuclear receptor protein PPARγ (30). As shown in Figure 5A, PPARγ expression was maintained in polyp tissue in the absence of sulindac treatment.…”

Section: Resultsmentioning

confidence: 99%

“…For example, sulindac can bind to and activate peroxisome proliferator-activated receptors (PPARs γ or δ), which have been shown to act as either a tumor suppressor or oncogene in colon cancer, respectively (28, 29). Also, in prostate cells, it has been shown that PPARγ is required for both growth inhibition and p21 up-regulation by sulindac sulfide (30). …”

Section: Introductionmentioning

confidence: 99%

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Molecular Alterations Associated with Sulindac-Resistant Colon Tumors in ApcMin/+ Mice

Greenspan

Nichols

Rosenberg

2010

Cancer Prevention Research

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Although nonsteroidal anti-inflammatory drugs (NSAID), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer, results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study, we evaluated the effect of sulindac on colon tumorigenesis in the Apc Min/+ mouse model. Sulindac (180 ppm) given in drinking water for 9 weeks to Apc Min/+ mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 versus 1.6 tumors per mouse, respectively; P < 0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. As expected, in the small intestine, sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 versus 42.0 tumors per mouse, respectively; P < 0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to exert its growth inhibitory effects through regulation of many noncyclooxygenase targets, including p21, β-catenin, E-cadherin, mitochondrial apoptotic proteins, and peroxisome proliferator-activated receptor-γ. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear β-catenin accumulation. Importantly, p21 WAF1/cip1 and peroxisome proliferatoractivated receptor-γ expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. Together, these observations may be translatable to designing novel clinical therapies using combinations of agents that target multiple molecular pathways to overcome sulindac resistance. Cancer Prev Res; 3(9);

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Alterations Associated with Sulindac-Resistant Colon Tumors in ApcMin/+ Mice

Greenspan

Nichols

Rosenberg

2010

Cancer Prevention Research

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“…For example, pioglitazone, a PPARg agonist inhibited p21-mediated prostate cancer cell growth (Hirsch et al, 2011). PPARg stimulates sulindac sulfide-mediated p21 expression in prostate epithelial cells (Jarvis et al, 2005). Soy peptide increased p21 in human breast MCF-7 tumour cells via inactivation of NF-kB, and thus inhibited their growth (Park et al, 2009).…”

Section: Figurementioning

confidence: 99%

“…NF-kB and PPARg are also important in p21-mediated cell cycle arrest of human cancer cells (Hellin et al, 2000;Prakobwong et al, 2011); the expression of p21 is increased in the resistant human cancer cells in a NF-kB-and PPARg-dependent manner (Chang and Miyamoto, 2006;Jarvis et al, 2005). Moreover, many investigators, using components and crude extracts isolated from the Magnolia family, have shown that p21-mediated cell cycle arrest leads to cell growth inhibition (Hahm and Singh, 2007;Lee et al, 2007;.…”

Section: Introductionmentioning

confidence: 99%

4‐O‐methylhonokiol, a PPARγ agonist, inhibits prostate tumour growth: p21‐mediated suppression of NF‐κB activity

Lee

Ban

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEThe effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, were investigated on human prostate cancer cells and its mechanism of action elucidated. EXPERIMENTAL APPROACHThe anti-cancer effects of MH were examined in prostate cancer and normal cells. The effects were validated in vivo using a mouse xenograft model. KEY RESULTSMH increased the expression of PPARg in prostate PC-3 and LNCap cells. The pull-down assay and molecular docking study indicated that MH directly binds to PPARg. MH also increased transcriptional activity of PPARg but decreased NF-kB activity. MH inhibited the growth of human prostate cancer cells, an effect attenuated by the PPARg antagonist GW9662. MH induced apoptotic cell death and this was related to G0-G1 phase cell cycle arrest. MH increased the expression of the cell cycle regulator p21, and apoptotic proteins, whereas it decreased phosphorylation of Rb and anti-apoptotic proteins. Transfection of PC3 cells with p21 siRNA or a p21 mutant plasmid on the cyclin D1/ cycline-dependent kinase 4 binding site abolished the effects of MH on cell growth, cell viability and related protein expression. In the animal studies, MH inhibited tumour growth, NF-kB activity and expression of anti-apoptotic proteins, whereas it increased the transcriptional activity and expression of PPARg, and the expression of apoptotic proteins and p21 in tumour tissues. CONCLUSIONS AND IMPLICATIONMH inhibits growth of human prostate cancer cells through activation of PPARg, suppression of NF-kB and arrest of the cell cycle. Thus, MH might be a useful tool for treatment of prostate cancer. AbbreviationCDK, cycline-dependent kinase; CNBr, cyanogen bromide; DAPI, 4',6-diamidino-2-phenylindole; GSK-3 b, glycogen synthase kinase 3 b; IAP1, inhibitor of apoptosis 1; iNOS, inducible NOS; MH, 4-O-methylhonokiol

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“…Regardless, the potential for 'receptor crossover' suggests that the ratio of PPARγ to PPARδ expression could alter both tumor biology and drug pharmacology. This is particular alarming given that the two receptors are co-expressed in most breast cancers and PPARδ has been implicated in promoting development and expansion of tumors from several tissue origins [24][25][26][27]. Clearly, an understanding of the role of each receptor in regulating growth of cancer cells should allow for future development of safer, yet effective PPAR modulators with potential therapeutic use for cancer.…”

Section: Introductionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor as a Therapeutic Target in Human Breast Cancer

Hall

Robinson²

2015

J Steroids Hormon Sci

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Objective: Peroxisome proliferator-activated receptor γ (PPARγ) is aberrantly expressed in most breast tumors, suggesting the potential of agents that target this receptor in treatment and chemoprevention of breast cancer. However, whether PPARγ leads to the promotion or reduction of tumor formation has remained controversial and is further complicated by the ability of its available thiazolidinedione (TZD) ligands to activate another PPAR subtype, PPARδ. Method:To examine the role of each receptor in breast cancer biology, we performed a systematic evaluation of PPARγ and PPARδ agonists on the growth of human estrogen receptor (ER)-positive and -negative breast cancer cells. Results:In this manner we found that TZD-activated PPARγ was highly effective in suppressing the proliferation of estrogen-dependent cancer cells. Activated PPARδ, however, displayed growth-enhancing effects independent of estradiol and regardless of the ER status of the cells. Strikingly, in ER-negative cancer cells expressing a favorable PPARδ/γ ratio, TZDs promoted growth in a PPAR γ-independent manner by direct activation of PPARδ. A screen for ligands with increased receptor selectivity compared to TZDs revealed that GW7845 functioned as a full agonist of PPARγ, yet this agent lacked the ability to activate PPARδ and elicit its associated mitogenic effects. Conclusion:These studies indicate that selective PPAR γ modulators (SPPARγMs) that lack agonist activity on PPARδ may be clinically useful in future cancer treatment and chemoprevention.

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Both PPARγ and PPARδ influence sulindac sulfide-mediated p21WAF1/CIP1 upregulation in a human prostate epithelial cell line

Cited by 28 publications

References 18 publications

Molecular Alterations Associated with Sulindac-Resistant Colon Tumors in ApcMin/+ Mice

Molecular Alterations Associated with Sulindac-Resistant Colon Tumors in ApcMin/+ Mice

4‐O‐methylhonokiol, a PPARγ agonist, inhibits prostate tumour growth: p21‐mediated suppression of NF‐κB activity

Peroxisome Proliferator-Activated Receptor as a Therapeutic Target in Human Breast Cancer

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