15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells

Abstract

Activation of peroxisome proliferator-activated receptor gamma (PPARg) has been linked to induction of differentiation, cell growth inhibition and apoptosis in several types of human cancer. However, the possible effects of PPARg agonists on human oral squamous cell carcinoma have not yet been reported. In this study, treatment with 15-deoxy-D 12,14 -PGJ 2 (15-PGJ 2 ), a natural PPARg ligand, induced a significant reduction of oral squamous cell carcinoma cell growth, which was mainly attributed to upregulation of apoptosis. Interestingly, rosiglitazone and ciglitazone, two members of the thiazolidinedione family of PPARg activators, did not exert a growth inhibitory effect. Given the critical role that the oncogene signal transducer and activator of transcription 3 (Stat3) plays in head and neck carcinogenesis, its potential regulation by PPARg ligands was also examined. Treatment of oral squamous cell carcinoma cells with 15-PGJ 2 induced an initial reduction and eventual elimination of both phosphorylated and unphosphorylated Stat3 protein levels. In contrast, other PPARg did not induce similar effects. Our results provide the first evidence of significant antineoplastic effects of 15-PGJ 2 on human oral squamous cell carcinoma cells, which may be related to downmodulation of Stat3 and are at least partly mediated through PPARg-independent events.

Abrogation of IL-6-mediated JAK signalling by the cyclopentenone prostaglandin 15d-PGJ2 in oral squamous carcinoma cells

“…Similarly, we recently demonstrated that 15d-PGJ 2 inhibits cell growth and induces apoptosis in oral SCC utilising PPARg-independent mechanisms (Nikitakis et al, 2002). Moreover, we suggested that the effects of 15d-PGJ 2 on oral SCC cells may be related to its ability to downregulate Stat3 (Nikitakis et al, 2002). In the present study, we investigated the effect of 15d-PGJ 2 on tyrosine kinases that regulate growth and survival of oral SCC cells, including JAKs and EGFR.…”

“…These effects, frequently attributed to activation of peroxisome proliferator-activated receptor gamma (PPARg), have been recently proven to be at least partially mediated through PPARg-independent pathways (Clay et al, 2001(Clay et al, , 2002Straus and Glass, 2001;Hsiang and Straus, 2002;Liu et al, 2003). Similarly, we recently demonstrated that 15d-PGJ 2 inhibits cell growth and induces apoptosis in oral SCC utilising PPARg-independent mechanisms (Nikitakis et al, 2002). Moreover, we suggested that the effects of 15d-PGJ 2 on oral SCC cells may be related to its ability to downregulate Stat3 (Nikitakis et al, 2002).…”

Requirement of Histone Deacetylase Activity for Signaling by STAT1

“…Curcumin, an anti-inflammatory and a chemopreventive agent, negatively regulates JAK/STAT1 signaling through activation of SHP-2 (61). Sulindac, a chemopreventive agent used to prevent polyp formation in familial adenomatous polyposis patients, inhibits constitutive STAT3 activation in human oral squamous cell carcinoma (62), suggesting that sulindac induces cell death and inhibits cell proliferation at least in part through the inhibition of constitutive activation of STAT3 (63)(64)(65)(66)(67). Agonists of PPAR␥, 15d-PGJ2, and the antidiabetic rosiglitazone have been shown to suppress JAK/STAT signal- ing through the induction of SOCS1 and SOCS3, which are suppressors of cytokine signaling (38).…”

The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells

“…Target mRNA values were normalized by using ␤-actin mRNA as an internal control. The relative quantitation of gene expression was performed by using the comparative ⌬⌬C t (threshold method) with ␤-actin as an internal control (20).…”