We previously demonstrated that nicotine stimulates non small cell lung carcinoma (NSCLC) cell proliferation through nicotinic acetylcholine receptor (nAChR)-mediated signals. Activation of peroxisome proliferator-activated receptor beta/delta (PPAR\#946;/\#948;) has also been shown to induce NSCLC cell growth. Here, we explore the link between nicotine and PPAR\#946;/\#948; and demonstrate that nicotine increased the expression of PPAR\#946;/\#948; protein; this effect was blocked by a \#945;7 nAChR antagonist (\#945;-bungarotoxin), by \#945;7 nAChR siRNA, and by inhibitors of PKC (Calphostin C), PI3-K (LY294002), and mTOR (rapamycin) signaling. In contrast, the effect was enhanced by PUN282987, an \#945;7 nAChR agonist. Silencing of PPAR\#946;/\#948; attenuated the stimulatory effect of nicotine on cell growth, but his was overcome by transfection of cells with an exogenous PPAR\#946;/\#948; expression vector. Of note, nicotine induced complex formation between \#945;7 nAChR and PPAR\#946;/\#948; protein, which required recruitment of the PPAR co-activator, PGC-1\#945;. Furthermore, silencing of PGC-1\#945; diminished the stimulatory effect of nicotine on PPAR\#946;/\#948; protein expression. Nicotine also increased PPAR\#946;/\#948; promoter activity through inhibition of AP-2\#945; protein expression, and silencing of AP-2\#945; enhanced the stimulatory effect of nicotine. Electrophoretic gel mobility shift and ChIP assays showed that nicotine reduced AP-2\#945; binding to DNA sequences in the promoter region of PPAR\#946;/\#948; gene. In addition, silencing of Sp1 attenuated the effect of nicotine on PPAR\#946;/\#948;. Collectively, our results demonstrate that nicotine increases PPAR\#946;/\#948; gene expression through PGC-1\#945; and \#945;7 nAChR-mediated activation of PKC/PI3-K/mTOR signals that inhibit AP-2\#945; protein expression and DNA binding activity to the PPAR\#946;/\#948; gene promoter. This study unveils a novel mechanism by which nicotine promotes human lung carcinoma cell survival.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5309.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO