Signal transducers and activators of transcription (STATs) were originally discovered as latent cytoplasmic transcription factors that mediate cellular responses to diverse cytokines and growth factors (for reviews, see references 17, 18, and 55). STATs are activated by tyrosine phosphorylation, dimerize, and subsequently translocate to the nucleus, where they regulate the transcription of genes by binding to specific DNA response elements. Studies have implicated normal STAT signaling in controlling fundamental biological processes, including cell differentiation, proliferation, apoptosis, and development (7,15,26,33,60,78). Multiple signaling pathways are simultaneously induced in response to cytokine or growth factor stimulation, consistent with complex regulation by signal cross talk. For example, maximum transcriptional activity of certain STATs requires serine phosphorylation mediated by serine/threonine kinases of other signaling pathways (3,19,51,68). The kinases that mediate STAT serine phosphorylation are not fully defined, although evidence implicates multiple serine kinase signals, including mitogen-activated protein kinases (MAPKs)/extracellular signal-regulated kinases (ERKs) (19), an H7-sensitive serine kinase (5), and a MAPK kinase (MKK)-dependent, ERK-independent serine kinase (11).MAPKs represent a family of serine/threonine protein kinases comprising ERK1/ERK2 (ERKs), p38/HOG1 (p38), and c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) (reviewed in references 24, 43, and 59). Ras and Raslike small G proteins are key regulators in the signaling pathways leading to MAPK activation. For the Ras-ERK branch, sequential protein phosphorylations are mediated by the serine/threonine kinase Raf-1 and the dual-specificity MKKs, which in turn phosphorylate and activate ERKs (24,48,49,72). For the JNK and p38 pathways, the Rac1/Cdc42 subfamily of small G proteins is a key mediator, together with Ras (for reviews, see references 24, 43, and 59). Several serine/threonine protein kinases that are members of the mixed-lineage kinases (MLK), such as dual leucine-zipper bearing kinase (DLK), have been identified as upstream activators of MKKs (23,24,38). Activation of JNK is largely induced by MKK4 and MKK7, while MKK3 and MKK6 preferentially activate p38 (22,24,62,75). Activated MAPKs ultimately phosphorylate transcription factors in the nucleus that are responsible for the regulation of immediate-early genes, such as c-fos, whose functional roles include control of cell proliferation (35,37,71).Emerging evidence strongly implicates abnormal activation of STAT signaling in oncogenic transformation. Our laboratory and others have previously reported constitutively active

Resveratrol is a naturally occurring phytoalexin with antioxidant and antiinflammatory properties. Recent studies suggest that resveratrol possesses anticancer effects, although its mechanism of action is not well understood. We now show that resveratrol inhibits Src tyrosine kinase activity and thereby blocks constitutive signal transducer and activator of transcription 3 (Stat3) protein activation in malignant cells. Analyses of resveratrol-treated malignant cells harboring constitutively-active Stat3 reveal irreversible cell cycle arrest of v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), human breast (MDA-MB-231), pancreatic (Panc-1), and prostate carcinoma (DU145) cell lines at the G 0 -G 1 phase or at the S phase of human breast cancer (MDA-MB-468) and pancreatic cancer (Colo-357) cells, and loss of viability due to apoptosis. By contrast, cells treated with resveratrol, but lacking aberrant Stat3 activity, show reversible growth arrest and minimal loss of viability. Moreover, in malignant cells harboring constitutively-active Stat3, including human prostate cancer DU145 cells and v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), resveratrol treatment represses Stat3-regulated cyclin D1 as well as Bcl-x L and Mcl-1 genes, suggesting that the antitumor cell activity of resveratrol is in part due to the blockade of Stat3-mediated dysregulation of growth and survival pathways. Our study is among the first to identify Src-Stat3 signaling as a target of resveratrol, further defining the mechanism of antitumor cell activity of resveratrol and raising its potential application in tumors with an activated Stat3 profile.

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