Haura EB, Turkson J, Jove R.. Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol 2: 315-324
Thoracic Oncology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.Nature Clinical Practice Oncology (Impact Factor: 8). 07/2005; 2(6):315-24. DOI: 10.1038/ncponc0195
Members of the signal transducers and activators of transcription (STAT) pathway, which were originally identified as key components linking cytokine signals to transcriptional events in cells, have recently been demonstrated to have a major role in cancer. They are cytoplasmic proteins that form functional dimers with each other when activated by tyrosine phosphorylation. Activated STAT proteins translocate to the nucleus to regulate expression of genes by binding to specific elements within gene promoters. Constitutive activation of the STAT family members Stat3 and Stat5, and/or loss of Stat1 signaling, is found in a large group of diverse tumors. Increasing evidence demonstrates that STAT proteins can regulate many pathways important in oncogenesis including cell-cycle progression, apoptosis, tumor angiogenesis, tumor-cell invasion and metastasis, and tumor-cell evasion of the immune system. Based on these findings, a growing effort is underway to target STAT proteins directly and indirectly for cancer therapy. This review will highlight STAT signaling pathways, STAT target genes involved in cancer, evidence for STAT activation in human cancers, and therapeutic strategies to target STAT molecules for anticancer therapy.
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- "). To investigate this hypothesis, we examined the effect of these compounds on key protein tyrosine kinases that phosphorylate and activate STAT3, namely, the nonreceptor tyrosine kinases Src and cAbl, and the receptor-associated Janus tyrosine kinase (JAK2) (Turkson et al., 1998; Haura et al., 2005; Srinivasan et al., 2008; Hedvat et al., 2009). Specifically, activation of Src and cAbl were examined through assessing levels of an activating phosphorylation of Src (p-Src Y416 ), an inactivating phosphorylation of Src (p-Src Y527 ) (Hunter, 1987), and an activating phosphorylation of cAbl (p-cAbl Y245 ) (Brasher Fig. 7. Pretreatment of PANC-1 and DU145 cells with Dp44mT or DpC inhibits IL-6–induced nuclear translocation of p-STAT3. "
ABSTRACT: Pharmacological manipulation of metal pools in tumor cells is a promising strategy for cancer treatment. Here, we reveal the iron-binding ligands, desferrioxamine (DFO), di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), inhibit constitutive and interleukin 6 (IL6)-induced activation of signal transducer and activator of transcription 3 (STAT3) signaling, which promotes proliferation, survival and metastasis of cancer cells. We demonstrate that DFO, Dp44mT, and DpC significantly decrease constitutive phosphorylation of the STAT3 transcription factor at Tyr705 in the pancreatic cancer cell lines, PANC-1 and MIAPaCa-2, as well as the prostate cancer cell line, DU145. These compounds also significantly decrease dimerized STAT3 levels, binding of nuclear STAT3 to its target DNA, and expression of downstream targets of STAT3, including cyclin D1, c-myc and Bcl-2. Examination of upstream mediators of STAT3 in response to these ligands revealed Dp44mT and DpC could significantly decrease activation of the non-receptor tyrosine kinase, Src, and activation of cAbl in DU145 and MIAPaCa-2 cells. In contrast to the effects of Dp44mT, DpC or DFO on inhibiting STAT3 activation, the negative control compound, di-2-pyridylketone 2-methyl-3-thiosemicarbazone (Dp2mT), or the DFO:Fe complex, which cannot bind cellular iron, had no effect. This demonstrates the role of iron-binding in the activity observed. Immunohistochemical staining of PANC-1 tumor xenografts showed a marked decrease in STAT3 in the tumors of mice treated with Dp44mT or DpC, compared to the vehicle. Collectively, these studies demonstrate suppression of STAT3 activity by iron depletion in vitro and in vivo, and reveal insights into regulation of the critical oncogenic STAT3 pathway. The American Society for Pharmacology and Experimental Therapeutics.
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- "Jenkins et al (5) found that STAT-3 deletion mutants completely reversed the splenomegaly, hepatic acute phase reaction, abnormal lymphocyte activation and spontaneous gastric antrum cancer observed in gp130 mutant mice, demonstrating that the sustained activation of STAT-3 is important for the abnormal proliferation of a variety of cells. Haura et al (6) showed that the expression of the STAT-3 mutant, STAT-3-C (with cysteine substitutions at amino acids at A661 and N663), is carcinogenic, further confirming that the sustained activation of STAT-3 leads to cell transformation, which is closely associated with human carcinogenesis. In the present study, the diethylnitrosamine (DEN)-induced rat liver cancer model was used to simulate the induction and development of human liver cancer. "
ABSTRACT: The aim of the present study was to investigate the expression of proteins associated with the sustained activation of the signal transducer and activator of transcription (STAT)-3 pathway during diethylnitrosamine (DEN)-induced rat liver carcinogenesis. DEN was intermittently administered to rats to induce liver cancer, and light and electron microscopy were used to observe the morphological changes in the liver during carcinogenesis. Western blotting and quantitative polymerase chain reaction (qPCR) were used to detect the expression of STAT-3, phosphorylated (p)-STAT-3, matrix metalloproteinase (MMP)-10, vascular endothelial growth factor (VEGF), kinase insert domain receptor (KDR), hypoxia inducible factor (HIF)-1α, basic fibroblast growth factor (bFGF) and interleukin (IL)-10, in order to investigate the association between STAT-3 and p-STAT-3 expression and MMP-10, VEGF, KDR, HIF-1α, bFGF and IL-10. The western blotting and qPCR results revealed that the expression of STAT-3, p-STAT-3, MMP-10, VEGF, KDR, HIF-1α, bFGF and IL-10 proteins gradually increased during carcinogenesis. Furthermore, the STAT-3 and p-STAT-3 levels were found to positively correlate with MMP-10, VEGF, KDR, HIF-1α, bFGF and IL-10 protein expression. During DEN-induced rat liver carcinogenesis, STAT-3 protein continually activated MMP-10, VEGF, KDR, HIF-1α, bFGF and IL-10, and its expression was found to positively correlate with the expression of these proteins.
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- "In OvCa, increased STAT3 directed transcription has been implicated in the stimulation of proliferation seen in response to cytokines, including VEGF and IL-6, in invasiveness  and as a predictor of poor prognosis . It activates the transcription of a number of genes, including antiapoptotic proteins Bcl-2, Bcl-xL and Mcl-1 , , . Moreover, constitutive activation of the STAT3 pathway has recently been shown to confer resistance to chemotherapy-induced apoptosis in epithelial malignancies –. "
ABSTRACT: This study examines the role of s-nitrosylation in the growth of ovarian cancer using cell culture based and in vivo approaches. Using the nitrosylating agent, S-nitrosoglutathione (GSNO), a physiological nitric oxide molecule, we show that GSNO treatment inhibited proliferation of chemoresponsive and chemoresistant ovarian cancer cell lines (A2780, C200, SKVO3, ID8, OVCAR3, OVCAR4, OVCAR5, OVCAR7, OVCAR8, OVCAR10, PE01 and PE04) in a dose dependent manner. GSNO treatment abrogated growth factor (HB-EGF) induced signal transduction including phosphorylation of Akt, p42/44 and STAT3, which are known to play critical roles in ovarian cancer growth and progression. To examine the therapeutic potential of GSNO in vivo, nude mice bearing intra-peritoneal xenografts of human A2780 ovarian carcinoma cell line (2×106) were orally administered GSNO at the dose of 1 mg/kg body weight. Daily oral administration of GSNO significantly attenuated tumor mass (p<0.001) in the peritoneal cavity compared to vehicle (phosphate buffered saline) treated group at 4 weeks. GSNO also potentiated cisplatin mediated tumor toxicity in an A2780 ovarian carcinoma nude mouse model. GSNO's nitrosylating ability was reflected in the induced nitrosylation of various known proteins including NFκB p65, Akt and EGFR. As a novel finding, we observed that GSNO also induced nitrosylation with inverse relationship at tyrosine 705 phosphorylation of STAT3, an established player in chemoresistance and cell proliferation in ovarian cancer and in cancer in general. Overall, our study underlines the significance of S-nitrosylation of key cancer promoting proteins in modulating ovarian cancer and proposes the therapeutic potential of nitrosylating agents (like GSNO) for the treatment of ovarian cancer alone or in combination with chemotherapeutic drugs.
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