PPARγ agonists attenuate proliferation and modulate Wnt/β-catenin signalling in melanoma cells

Smith, Aaron G.; Beaumont, Kimberley A.; Smit, Darren J.; Thurber, Amy E.; Cook, Anthony; Boyle, Glen M.; Parsons, Peter G.; Sturm, Richard A.; Muscat, George E.O.

doi:10.1016/j.biocel.2008.08.037

Cited by 32 publications

(30 citation statements)

References 52 publications

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“…One possible mechanism might involve downregulation of the Wnt/b-catenin pathway because this pathway is inhibited by some PPARg agonists and might mediate the inhibition of MITF expression. 17,18 Thus, considering all our results we show for the first time that the control of MITF expression by ciglitazone is involved in the inhibition of CXCL1 expression and secretion. This new signaling pathway involves MITF in the regulation of CXCL1 and strengthens the importance of this transcription factor in melanoma tumorigenicity.…”

Section: Discussionmentioning

confidence: 99%

“…To further investigate the mechanism responsible for ciglitazone-induced CXCL1 downregulation, we focused our attention on MITF that was recently reported to be regulated by some PPARg agonists. 17,18 Ciglitazone induced a dose-dependent reduction of MITF expression in both A375 and SK-Mel-28 melanoma cells (Figure 7a). We demonstrated that MITF inhibition by ciglitazone was not due to its cleavage during Cytokines Chemokine (C-X-C motif) ligand 1 (melanoma growth-stimulating activity, a) Negative regulation of MITF/CXCL1 axis by TZD T Botton et al apoptosis because the MITF decrease was observed earlier than PARP cleavage.…”

Section: Resultsmentioning

confidence: 99%

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Ciglitazone negatively regulates CXCL1 signaling through MITF to suppress melanoma growth

et al. 2010

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We have previously demonstrated that the thiazolidinedione ciglitazone inhibited, independently of PPARc activation, melanoma cell growth. Further investigations now show that ciglitazone effects are mediated through the regulation of secreted factors. Q-PCR screening of several genes involved in melanoma biology reveals that ciglitazone inhibits expression of the CXCL1 chemokine gene. CXCL1 is overexpressed in melanoma and contributes to tumorigenicity. We show that ciglitazone induces a diminution of CXCL1 level in different human melanoma cell lines. This effect is mediated by the downregulation of microphthalmia-associated transcription factor, MITF, the master gene in melanocyte differentiation and involved in melanoma development. Further, recombinant CXCL1 protein is sufficient to abrogate thiazolidinedione effects such as apoptosis induction, whereas extinction of the CXCL1 pathway mimics phenotypic changes observed in response to ciglitazone. Finally, inhibition of human melanoma tumor development in nude mice treated with ciglitazone is associated with a strong decrease in MITF and CXCL1 levels. Our results show that anti-melanoma effects of thiazolidinediones involve an inhibition of the MITF/ CXCL1 axis and highlight the key role of this specific pathway in melanoma malignancy. Cell Death and Differentiation (2011) 18, 109-121; doi:10.1038/cdd.2010.75; published online 2 July 2010Cutaneous melanoma is an aggressive skin cancer that originates from epidermal melanocytes. Melanoma development is accomplished through the accumulation of genetic alterations in growth control pathways including oncogenic mutations or gene amplification. For example, constitutive activation of the Ras/MAPkinase-signaling pathway is frequently observed in melanomas, as a consequence of activating mutations of the B-Raf and N-Ras genes. 1-3Melanoma progression is also accompanied by generation of autocrine and paracrine loops associated with the aberrant production and secretion of growth factors and chemokines that sustain growth, survival and invasion. 4 In humans, melanoma is one of the most lethal cancers among young adults. Melanoma has a high capability of invasion and rapid metastasis to other organs. The prognosis of metastatic melanoma is extremely dismal, as the various treatments have not shown survival benefit.5 It appears thus necessary to develop approaches enabling the discovery of new molecular targets, candidates for specific biotherapy treatment of this disease.Thiazolidinediones (TZDs) regulate transcriptional activity of the nuclear receptor peroxysome proliferator activated receptor g (PPARg) and are currently used in type II diabetes treatment. More recently, TZD have been reported to inhibit proliferation and survival of numerous cancer cells. 6 Furthermore, we have previously demonstrated that ciglitazone, which belongs to TZD family, inhibits growth and viability of melanoma cells without affecting normal melanocyte growth. 7To further investigate the molecular events elicited by ciglitazone and to b...

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Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Ciglitazone negatively regulates CXCL1 signaling through MITF to suppress melanoma growth

et al. 2010

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“…13,14 Troglitazone induced apoptosis of PC-3 and LNCaP prostate cancer cells through inhibition of bcl-x L /bcl-2 expression via PPARγ independent manner. 15 Several reports suggest that troglitazone, rosiglitazone and piogliazone may have pharmacological effects through GSK-3β inhibition.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

“…However, it has recently been demonstrated that PPARγ ligands can exert PPARγ-independent biological responses including growth arrest and apoptosis in selected carcinoma types. [13][14][15] We thus first tested effects of troglitazone on prostate cancer cell growth and PPARγ expression. Treatment of troglitazone inhibited cancer cell growth in PC-3 and LNCaP prostate cancer cells in a dosedependent manner with similar extent.…”

confidence: 99%

“…However, PPARγ independent cancer cell growth inhibition has been also reported. [13][14][15] Several reports demonstrate that anticancer effect of PPARγ agonists may be related with the modulation of expression or activating of glycogen synthase kinase-3 (GSK-3β) and/or nuclear factor kappa B (NFκB). Among the several GSK-3 isoforms, GSK-3α and GSK-3β are serine/threonine kinases involved in several cell growth signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

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Troglitazone, a PPAR agonist, inhibits human prostate cancer cell growth through inactivation of NFκB via suppression of GSK-3β expression

Ban¹,

Oh²,

Son³

et al. 2011

Cancer Biology & Therapy

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Proteome Analysis Identified the PPARγ Ligand 15d-PGJ2 as a Novel Drug Inhibiting Melanoma Progression and Interfering with Tumor-Stroma Interaction

Paulitschke

Gruber

Hofstätter

et al. 2013

Evolution-Adjusted Tumor Pathophysiology:

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PPARγ agonists attenuate proliferation and modulate Wnt/β-catenin signalling in melanoma cells

Cited by 32 publications

References 52 publications

Ciglitazone negatively regulates CXCL1 signaling through MITF to suppress melanoma growth

Ciglitazone negatively regulates CXCL1 signaling through MITF to suppress melanoma growth

Troglitazone, a PPAR agonist, inhibits human prostate cancer cell growth through inactivation of NFκB via suppression of GSK-3β expression

Proteome Analysis Identified the PPARγ Ligand 15d-PGJ2 as a Novel Drug Inhibiting Melanoma Progression and Interfering with Tumor-Stroma Interaction

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