Abstract 3816: Comparative cellular effects of 4-phenyl-3-butenoic acid and suberoylanilide acid in tumorigenic and non-tumorigenic cells

Abstract

Abstract 4-phenyl-3-butenoic acid (PBA) is a small molecule anti-inflammatory agent which was previously shown to inhibit growth, increase gap junction intercellular communication, increase phosphorylation of p38 mitogen activated protein kinase (p38 MAPK), and decrease phosphorylation of c-Jun N-terminal Kinase (JNK) in tumorigenic cells at concentrations that do not similarly affect non-tumorigenic cells. Suberoylanilide acid (SAHA), which is also known as vorinostat, is a relatively new anticancer agent structurally similar to PBA. The purpose of this study was to compare the effects of these two agents on JNK and p38 activation in vitro, as well as on cell growth. p38 MAPK and JNK are stress-activated members of the MAPK family that play important roles in the control of cell proliferation in a wide variety of cell types. Altered expression or activation of these MAPKs has been observed in numerous tumorigenic cells and human cancers. Our studies utilized human lung carcinoma cells (H2009), transformed rat liver epithelial cells (WB-ras) as well as non-tumorigenic cells from the same line (WB-neo). Cells were grown to 60-70% confluence and were subjected to treatment with PBA (0.1 mg/ml), SAHA (500 nM) or vehicle for 48 hours. Whole cell lysates were extracted and individual proteins were separated by SDS-PAGE, followed by western blotting using phosphorylation site-specific antibodies to p38 and JNK proteins. For cell counting, cells were trypsinized and suspended followed by counting utilizing a Biorad TC-10TM cell counter. PBA and SAHA were shown to have similar effects on JNK and p38 MAPK phosphorylation in tumorigenic WB-ras and H2009 cell lines. These effects included an increase in p38 MAPK phosphorylation and a decrease in JNK phosphorylation. Both compounds were shown to significantly decrease cell growth under these conditions. In untransformed WB-neo cells significant differences in p38 MAPK phosphorylation were not seen with either treatment. However it was shown that a decrease in phosphorylation of JNK occurred following SAHA treatment, but not PBA treatment in the WB-neo cells. Overall these studies demonstrate that PBA has similar effects on JNK and p38 MAPK compared to SAHA in tumorigenic cells, while being less potent in the non-tumorigenic WB-neo cells. This earmarks PBA for further studies as a targeted anti-tumor therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3816. doi:1538-7445.AM2012-3816