Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D, Yoder S, Enkemann S, Eschrich S, Lee J, Beam C, Cheng J, Minton S, Muro-Cacho C, Jove RPersistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12: 11-19

University of South Florida, Tampa, Florida, United States
Clinical Cancer Research (Impact Factor: 8.72). 02/2006; 12(1):11-9. DOI: 10.1158/1078-0432.CCR-04-1752
Source: PubMed


Signal transducer and activator of transcription 3 (Stat3) protein is persistently activated in breast cancer and promotes tumor cell survival. To gain a better understanding of the role of constitutive Stat3 signaling in breast cancer progression, we evaluated the expression profile of potential Stat3-regulated genes that may confer resistance to apoptosis.
Stat3 signaling was blocked with antisense oligonucleotides in human MDA-MB-435s breast cancer cells and Affymetrix GeneChip microarray analysis was done. The candidate Stat3 target gene Survivin was further evaluated in molecular assays using cultured breast cancer cells and immunohistochemistry of breast tumor specimens.
Survivin, a member of the inhibitor of apoptosis protein family, was identified as a potential Stat3-regulated gene by microarray analysis. This was confirmed in Survivin gene promoter studies and chromatin immunoprecipitation assays showing that Stat3 directly binds to and regulates the Survivin promoter. Furthermore, direct inhibition of Stat3 signaling blocked the expression of Survivin protein and induced apoptosis in breast cancer cells. Direct inhibition of Survivin expression also induced apoptosis. Increased Survivin protein expression correlates significantly (P = 0.001) with elevated Stat3 activity in primary breast tumor specimens from high-risk patients who were resistant to chemotherapy treatment.
We identify Survivin as a direct downstream target gene of Stat3 in human breast cancer cells that is critical for their survival in culture. Our findings suggest that activated Stat3 signaling contributes to breast cancer progression and resistance to chemotherapy by, at least in part, inducing expression of the antiapoptotic protein, Survivin.

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Available from: Carlos Muiro-Cacho, Nov 17, 2015
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    • "Earlier investigators showed that GO-Y030, curcumin analogue, inhibited colorectal carcinoma cell growth in vitro and in a mouse model [165] and this analogue also inhibits STAT3 activity and cell growth in the breast and pancreatic carcinomas [166]. The inhibition of STAT3 via GO-Y030 also plays an important role in downregulation of the expression of STAT3-regulated genes in colorectal cancer stem cells, such as Cyclin D1 [167], surviving [168], Bcl-2, and Bcl-XL [167, 169]. An important study showed that GO-Y030 reduced the STAT3 downstream target gene expression and induced apoptosis in colon cancer stem cells [170]. "
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    ABSTRACT: Cancer is the most dreadful disease worldwide in terms of morbidity and mortality. The exact cause of cancer development and progression is not fully known. But it is thought that cancer occurs due to the structural and functional changes in the genes. The current approach to cancer treatment based on allopathic is expensive, exhibits side effects; and may also alter the normal functioning of genes. Thus, a safe and effective mode of treatment is needed to control the cancer development and progression. Some medicinal plants provide a safe, effective and affordable remedy to control the progression of malignant cells. The importance of medicinal plants and their constituents has been documented in Ayurveda, Unani medicine, and various religious books. Curcumin, a vital constituent of the spice turmeric, is an alternative approach in the prevention of cancer. Earlier studies have shown the effect of curcumin as an antioxidant, antibacterial, antitumor and it also has a noteworthy role in the control of different diseases. In this review, we summarize the understanding of chemopreventive effects of curcumin in the prevention of cancer via the regulation of various cell signaling and genetic pathways.
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    • "Constitutive activation of STAT3 contribute to the upregulation of Bcl - xL in ovarian cancer cell lines that contributes to the survival advantage of human ovarian carcinoma ( Burke et al , 2001 ) . Activation of STAT3 signalling can also induce expression of survivin gene that was found to confer resistance to apoptosis in human breast cancer cells ( Gritsko et al , 2006 ) . Hence , tumour cells containing persistently activated STAT3 are more resistant to environmental apoptotic cues and conventional chemotherapies that rely on the apoptotic pathway for chemotherapy - induced cell death . "
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    ABSTRACT: Background: Constitutive activation of signal transducer and activator of transcription signalling 3 (STAT3) has been linked with survival, proliferation and angiogenesis in a wide variety of malignancies including hepatocellular carcinoma (HCC). Methods: We evaluated the effect of lupeol on STAT3 signalling cascade and its regulated functional responses in HCC cells. Results: Lupeol suppressed constitutive activation of STAT3 phosphorylation at tyrosine 705 residue effectively in a dose- and time-dependent manner. The phosphorylation of Janus-activated kinases (JAKs) 1 and 2 and Src was also suppressed by lupeol. Pervanadate treatment reversed the downregulation of phospho-STAT3 induced by lupeol, thereby indicating the involvement of a phosphatase. Indeed, we observed that treatment with lupeol increased the protein and mRNA levels of SHP-2, and silencing of SHP-2 abolished the inhibitory effects of lupeol on STAT3 activation. Treatment with lupeol also downregulated the expression of diverse STAT3-regulated genes and decreased the binding of STAT3 to VEGF promoter. Moreover, the proliferation of various HCC cells was significantly suppressed by lupeol, being associated with substantial induction of apoptosis. Depletion of SHP-2 reversed the observed antiproliferative and pro-apoptotic effects of lupeol. Conclusions: Lupeol exhibited its potential anticancer effects in HCC through the downregulation of STAT3-induced pro-survival signalling cascade.
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    • "Our previous studies also showed that survivin is a key mediator for MEC cell lines and several compounds blocked survivin during apoptotic cell death.[2526] It was recently shown that constitutive activation of STAT3 can modify the expression level of survivin protein in malignant cells[2728] suggesting that survivin may be regulated by the STAT3 signaling pathway. Thus, we investigated the effects of CT on survivin and the results showed that CT clearly reduced the expression level of survivin protein at a transcriptional level evidenced by the suppression of mRNA and its promoter activity in response to CT. "
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    ABSTRACT: Background:Cryptotanshinone (CT) is a biologically active compound from the root of Salvia miltiorrhiza that has been reported to induce apoptosis in various cancer cell lines; but, it has not yet been fully explored in human mucoepidermoid carcinoma (MEC).Objective:Here, we demonstrated the apoptotic effects and its related mechanism in MC-3 and YD-15 human MEC cell lines.Materials and Methods:The effects of CT on apoptotic activity were evaluated by cell proliferation assay, Western blotting, 4’-6-diamidino-2-phenylindole staining, reverse transcription-polymerase chain reaction, and luciferase assay.Results:Our data show that CT treatment of MC-3 cells results in anti-proliferative and apoptotic activities in MC-3 and it is accompanied by a decrease in phosphorylation and dimerization of signal transducer and activators of transcription 3 (STAT3). CT decreased the expression levels of myeloid cell leukemia-1 (Mcl-1) and surviving, whereas Bcl-xL expression was not changed. CT clearly regulates survivin protein at a transcriptional level and alters Mcl-1 through proteasome-dependent protein degradation. In addition, CT-induced apoptotic cell death in YD-15, another human MEC cell line, was associated with the inhibition of STAT3 phosphorylation.Conclusion:These data suggest that CT could be a good apoptotic inducer through modification of STAT3 signaling in human MEC cell lines.
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