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.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to prevent colorectal tumorigenesis. Although antitumor effects of NSAIDs are mainly due to inhibition of cyclooxygenase activity, there is increasing evidence that cyclooxygenase-independent mechanisms may also play an important role. The early growth response-1 (EGR-1) gene is a member of the immediate-early gene family and has been identified as a tumor suppressor gene. Tolfenamic acid is a NSAID that exhibits anticancer activity in a pancreatic cancer model. In the present study, we investigated the anticancer activity of tolfenamic acid in human colorectal cancer cells. Tolfenamic acid treatment inhibited cell growth and induced apoptosis as measured by caspase activity and bioelectric impedance. Tolfenamic acid induced EGR-1 expression at the transcription level, and analysis of the EGR-1 promoter showed that a putative ETS-binding site, located at À400 and À394 bp, was required for activation by tolfenamic acid. The electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed that this sequence specifically bound to the ETS family protein epithelial-specific ETS-1 (ESE-1) transcription factor. Tolfenamic acid also facilitated translocation of endogenous and exogenous ESE-1 to the nucleus in colorectal cancer cells, and gene silencing using ESE-1 small interfering RNA attenuated tolfenamic acid-induced EGR-1 expression and apoptosis. Overexpression of EGR-1 increased apoptosis and decreased bioelectrical impedance, and silencing of endogenous EGR-1 prevented tolfenamic acid-induced apoptosis. These results show that activation of ESE-1 via enhanced nuclear translocation mediates tolfenamic acid-induced EGR-1 expression, which plays a critical role in the activation of apoptosis.
Resveratrol, a dietary phytoalexin readily available in the diet, is reported to possess antitumorigenic properties in several cancers, including colorectal. However, the underlying mechanism(s) involved is not completely understood. In the present study, we investigated the effect of resveratrol treatment on gene modulation in human colorectal cancer cells and identified activating transcription factor 3 (ATF3) as the most highly induced gene after treatment. We confirmed that resveratrol upregulates ATF3 expression, both at the mRNA and protein level, and showed resveratrol involvement in ATF3 transcriptional regulation. Analysis of the ATF3 promoter revealed the importance of early growth response-1 (Egr-1; located at À245 to À236) and Kr€ uppel-like factor 4 (KLF4; located at À178 to À174) putative binding sites in resveratrolmediated ATF3 transactivation. Specificity of these sites to the Egr-1 and KLF4 protein was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Resveratrol increased Egr-1 and KLF4 expression, which preceded ATF3 expression, and further suggests Egr-1 and KLF4 involvement in resveratrol-mediated activity. We provide evidence for Egr-1 and KLF4 interaction in the presence of resveratrol, which may facilitate ATF3 transcriptional regulation by this compound. Furthermore, we demonstrate that induction of apoptosis by resveratrol is mediated, in part, by increased ATF3 expression. Taken together, these results provide a novel mechanism by which resveratrol induces ATF3 expression and represent an additional explanation of how resveratrol exerts its antitumorigenic effects in human colorectal cancer cells.
Localized prostate cancer is distinctively characterized by intratumoral heterogeneity, and tumors with more complex evolutionary paths display more aggressive characteristics. In clinical trials of intense neoadjuvant androgen deprivation therapy (inADT), patients with complete or near-complete responses experience durable remissions. However, the molecular characteristics distinguishing exceptional responders and nonresponders at baseline have not been established. Here, we present the integrated histologic and genomic analysis of pre-treatment baseline tissue from our recent Phase 2 clinical study of inADT. Multiregion sampling demonstrated that patients with incomplete and nonresponding tumors demonstrate greater tumor diversity as estimated by phylogenetic tree reconstruction from DNA sequencing and automated analysis of immunohistochemical stains. Development of a four-factor binary model to predict poor response correlated with increased genomic diversity in our 37-patient cohort and a validation cohort of 188 Gleason score 8-10 prostate cancers. Together, these findings demonstrate that even in the primary setting, more highly evolved tumors have increased fitness to resist therapy.
PURPOSE Despite decreased screening-based detection of clinically insignificant tumors, most diagnosed prostate cancers are still indolent, indicating a need for better strategies for detection of clinically significant disease before treatment. We hypothesized that patients with detectable circulating tumor DNA (ctDNA) were more likely to harbor aggressive disease. METHODS We applied ultra-low-pass whole-genome sequencing to profile cell-free DNA from 112 patients diagnosed with localized prostate cancer and performed targeted resequencing of plasma DNA for somatic mutations previously identified in matched solid tumor in nine cases. We also performed similar analyses of data from patients with metastatic prostate cancer. RESULTS In all cases of localized prostate cancer, even in clinically high-risk patients who subsequently had recurrent disease, ultra-low-pass whole-genome sequencing and targeted resequencing did not detect ctDNA in plasma acquired before surgery or before recurrence. In contrast, using both approaches, ctDNA was detected in patients with metastatic prostate cancer. CONCLUSION Our findings demonstrate clear differences between localized and advanced prostate cancer with respect to the dissemination and detectability of ctDNA. Because allele-specific alterations in ctDNA are below the threshold for detection in localized prostate cancer, other approaches to identify cell-free nucleic acids of tumor origin may demonstrate better specificity for aggressive disease.
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