No abstract

Resveratrol (3, 4', 5-trihydroxystilbene), a naturally-occurring phytoalexin readily available in the diet, is reported to possess both chemopreventive and chemotherapeutic activities in several cancers. However, despite the identification of numerous molecular targets, the underlying mechanisms involved in the anticancer activities of resveratrol are not completely understood. Resveratrol is postulated to function as a potential signaling pathway modulator and as such, is demonstrated to affect a multitude of signal transduction pathways associated with tumorigenesis and/or carcinogenesis; it is likely that this collective activity, rather than just a single effect, may play an important role in the anticancer properties of resveratrol. Since transcription factors control the expression of many genes, the elucidation of molecular targets of resveratrol involved in transcriptional regulation is necessary to better understand how this dietary phytochemical affects chemopreventive and chemotherapeutic processes. As a result, investigators have increasingly searched for and examined possible targets of resveratrol. In this review, we summarize the current knowledge on molecular targets, specifically transcription factors, that contribute to the observed anticancer effects of resveratrol related to: (1) inhibition of carcinogenic activation and induction of carcinogen detoxification, (2) induction of growth arrest and apoptosis, and (3) suppression of pro-inflammatory signaling pathways related to cancer progression.

Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug associated with anti-tumorigenic and pro-apoptotic properties in animal and in vitro models of cancer. However, the underlying cellular mechanisms by which TA exerts its effects are only partially understood. Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic region-leucine zipper family and has been known as a tumor suppressor in human colorectal cancer cells. The present study was performed to observe whether ATF3 mediates TA-induced apoptosis and to elucidate the molecular mechanism of ATF3 transcription induced by TA. TA treatment and ectopic expression of ATF3 increased apoptosis whereas knockdown of ATF3 resulted in significant repression of TA-activated apoptosis. The TA treatment also induced ATF3 promoter activity. Internal deletion and point mutation of the predicted ATF/C/EBP binding site in ATF3 promoter abolished luciferase activation by TA. Overexpression of ATF2 resulted in significant increase of ATF3 promoter activity, and electrophoretic mobility shift assay identified this region as a core sequence to which ATF2 binds. TA treatment resulted in an increase of ATF2 phosphorylation, which was followed by a subsequent increase of ATF3 transcription. Knockdown of ATF2 abolished TA-induced ATF3 expression. We further provide evidence that TA leads to increases of phospho-p38 MAPK, JNK, and ERK levels. Inhibition of these pathways using selective inhibitors and dominant negative constructs ameliorated TA-induced ATF3 expression and promoter activities. The current study demonstrates that TA stimulates ATF3 expression and subsequently induces apoptosis. These pathways are mediated through phosphorylation of ATF2, which is mediated by p38 MAPK, JNK, and ERK-dependent pathways.