The c-Jun N-terminal kinase (JNK) signaling pathway controls many cellular processes such as cell growth, differentiation, and apoptosis. Aberrant JNK activity has been implicated in various cancer types including but not limited to hepatocellular carcinoma, glioblastoma, leukemia, and lung cancer, presumably through activation of the transcription factor activator protein-1 (AP-1). When activated by JNKs, AP-1 is a positive regulator of cell proliferation and many tumorigenic cell types are found to have increased JNK activity. Phosphorylated mitogen-activated protein kinase kinase 4 (pMKK4) and phosphorylated mitogen-activated protein kinase kinase 7 (pMKK7) are known to activate JNKs via phosphorylation. The purpose of this study was to determine the effects of 4-phenyl-3-butenoic acid (PBA) on JNK pathway proteins. PBA is a small molecule anti-inflammatory agent which was previously shown to inhibit growth, increase gap junction intercellular communication, and increase phosphorylation of p38 mitogen activated protein kinase (p38 MAPK) in tumorigenic cells at concentrations that do not similarly affect non-tumorigenic cells. Our studies utilized tumorigenic ras-transformed rat liver epithelial cells (WB-ras) and human lung carcinoma (H2009) cells. Cells were grown to confluence and were subjected to treatment with PBA (0.1 mg/ml) 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 JNK pathway proteins. Quantitative analysis of western blots was performed utilizing densitometry software. PBA attenuated phosphorylation of JNK approximately two-fold in both WB-ras and H2009 lung carcinoma cells. PBA also attenuated phosphorylation of the JNK downstream effector, activating transcription factor 2 (ATF-2). Phosphorylation of MKK4 was decreased following treatment with PBA, while phosphorylation of MKK7 was unaffected. This data suggests that PBA may inhibit growth of tumorigenic cells in part through decreased activation of the JNK pathway via a MKK4 mechanism.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2649. doi:10.1158/1538-7445.AM2011-2649