Phorbol ester potentiates the growth inhibitory effects of troglitazone via up-regulation of PPARgamma in A549 cells.
The activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to induce growth arrest and differentiation of various cancer cells. In the current study, we investigated the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the expression of PPARgamma and proliferation of A549 cells. TPA elicited a dose- and time-dependent increase in PPARgamma mRNA and protein levels. PPARgamma expression in response to TPA was attenuated by pretreatment with bisindolylmaleimide I, N-acetyl-L-cysteine (NAC) and PD98059. TPA-induced protein kinase C (PKC) activation was linked to the generation of reactive oxygen species (ROS), both of which were indispensable for PPARgamma expression in A549 cells. Pretreatment with bisindolylmaleimide I or NAC blocked TPA-induced phosphorylation of extracellular signal-regulated kinase (ERK), suggesting that ERK-mediated signaling is also involved in the induction of PPARgamma. Furthermore, the growth inhibitory effect of troglitazone was significantly potentiated by prolonged incubation with TPA and was attenuated in the presence of GW9662, a specific inhibitor of PPARgamma. These effects were associated with an induction of cell cycle arrest at G0/G1 phase, which was accompanied by the induction of p21Waf1/Cip1 expression and decreased cyclin D1 expression. Taken together, these observations indicate that TPA synergizes with PPARgamma ligand to inhibit cell growth through up-regulation of PPARgamma expression.
Kim
Hyo Jung
HJ
Department of Pharmacology, Gyeongsang Institute of Health Science, College of Medicine, Gyeongsang National University, Jinju 660-751, Republic of Korea.
Woo
Im Sun
IS
Kang
Eun Sil
ES
Eun
So Young
SY
Kim
Gil Hyeong
GH
Ham
Sun Ah
SA
Kim
Hye Jung
HJ
Lee
Jae Heun
JH
Chang
Ki Churl
KC
Kim
Jin-Hoi
JH
Lee
Hoon Taek
HT
Seo
Han Geuk
HG
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D019938:Cyclin D1 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047495:PPAR gamma / Q000096:biosynthesis*; D010703:Phorbol Esters / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D015854:Up-Regulation
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D002839:Chromans; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047495:PPAR gamma; D010703:Phorbol Esters; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077288:Troglitazone