Curcumin Inhibits Constitutive STAT3 Phosphorylation in Human Pancreatic Cancer Cell lines and Downregulation of Survivin/BIRC5 Gene Expression

Glienke, Wolfgang; Maute, Luise; Wicht, Johannes; Bergmann, Lothar

doi:10.3109/07357900903287006

Cited by 102 publications

(65 citation statements)

References 21 publications

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“…However, it should be noted that abrogation of Stat3 may have unexpected side effects since many genes are regulated by Stat3. Glienke et al reported that siRNA-mediated Stat3 knockdown not only induced apoptosis of pancreatic cancer cell lines BxPC-3 but also promoted the expression of anti-apoptotic genes Survivin/ BIRC5 and BCL-xL in the same cell lines [44]. The ideal goal is to find effective therapeutic agents that block Stat3 activity with negligible side effects.…”

Section: Discussionmentioning

confidence: 98%

Stat3 promotes invasion of esophageal squamous cell carcinoma through up-regulation of MMP2

Xuan

Lou

et al. 2014

Mol Biol Rep

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Stat3 alters the expression of its downstream genes and is associated with tumor invasion and metastasis in several human cancers. Its role in esophageal squamous cell carcinoma (ESCC) has not been well characterized. We examined the tumor sections of 100 cases of ESCC by immunohistochemistry and observed significant overexpression of Stat3 in the cytoplasm of 89% of ESCC cells and of phosphorylated Stat3 (p-Stat3) in the nuclei of 71% of ESCC when compare with normal esophageal mucosa (72%, p = 0.02; and 31%, p = 0.001). Overexpression of Stat3 and p-Stat3 positively correlated with that of matrix metalloproteinase-2 (MMP2), a known regulator for cell migration, in 65% of ESCC while only 26% shown in benign esophageal mucosa. To further investigate the association of Stat3 with tumor metastasis in vitro, invasion of EC-1 cells (a human ESCC cell line) were investigated with Boyden chambers. The results showed that transfection of Stat3 not only promoted invasion of EC-1 cells but also significantly induced MMP2 expression in a dose-dependent manner. In contrast, suppressing expression of endogenous Stat3 mRNA and protein by Stat3 siRNA significantly reduced EC-1 cell invasion and MMP2 expression. A high-affinity Stat3-binding element was localized to the positions of 648-641 bp (TTCTCGAA) in the MMP2 promoter with electrophoretic mobility shift assay. Our results suggest that Stat3, p-Stat3, and MMP2 were overexpressed in ESCC and associated with invasion of ESCC; and Stat3 up-regulated expression of MMP2 in ESCC through directly binding to the MMP2 promoter.

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Section: Discussionmentioning

confidence: 98%

Stat3 promotes invasion of esophageal squamous cell carcinoma through up-regulation of MMP2

Xuan

Lou

et al. 2014

Mol Biol Rep

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“…STAT3 activation was also associated in cancer (22,35) and systemic vascular remodeling (40) with an upregulation of Survivin mRNA levels. Survivin, a member of the inhibitor of apoptosis family of proteins, was described as a major player in PAH pathogenesis (39).…”

Section: Dhea and Stat3 Inhibition Reverses Mir-204 Downregulation Inmentioning

confidence: 99%

Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension

Paulin

Meloche

Jacob

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

114

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Paulin R, Meloche J, Jacob MH, Bisserier M, Courboulin A, Bonnet S. Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 301: H1798 -H1809, 2011. First published September 2, 2011; doi:10.1152/ajpheart.00654.2011.-Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This phenotype is sustained by the activation of the Src/signal transducer and activator of transcription 3 (STAT3) axis, maintained by a positive feedback loop involving miR-204 and followed by an aberrant expression/activation of its downstream targets such as Pim1 and nuclear factor of activated T-cells (NFATc2). Dehydroepiandrosterone (DHEA) is a steroid hormone shown to reverse vascular remodeling in systemic vessels. Since STAT3 has been described as modulated by DHEA, we hypothesized that DHEA reverses human pulmonary hypertension by inhibiting Src/STAT3 constitutive activation. Using PASMCs isolated from patients with PAH (n ϭ 3), we demonstrated that DHEA decreases both Src and STAT3 activation (Western blot and nuclear translocation assay), resulting in a significant reduction of Pim1, NFATc2 expression/activation (quantitative RT-PCR and Western blot), as well as Survivin and upregulation of bone morphogenetic protein receptor 2 (BMPR2) and miR-204. Src/STAT3 axis inhibition by DHEA is associated with 1) mitochondrial membrane potential (tetramethylrhodamine methyl-ester perchlorate; n ϭ 150; P Ͻ 0.05) depolarization increasing apoptosis by 25% (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling; n ϭ 150; P Ͻ 0.05); and 2) decreased intracellular Ca 2ϩ concentration (fluo-3 AM; n ϭ 150; P Ͻ 0.05) and proliferation by 30% (PCNA). Finally, in vivo similarly to STAT3 inhibition DHEA improves experimental PAH (monocrotaline rats) by decreasing mean PA pressure and right ventricle hypertrophy. These effects were associated with the inhibition of Src, STAT3, Pim1, NFATc2, and Survivin and the upregulation of BMPR2 and miR-204. We demonstrated that DHEA reverses pulmonary hypertension in part by inhibiting the Src/STAT3.

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“…17,18 Accumulating data indicated that most tumors express high levels of signal transducer and activator of transcription 3 (Stat3), which is known to upregulate the expression of Survivin. [19][20][21] Such upregulation in the absence of GRIM-19 may promote tumor growth and metastasis. We show here, for the first time, that co-expression of Survivin-shRNA and GRIM -19 protein from the same plasmid causes a synergistic suppression of prostate tumor growth in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Plasmid-based Survivin shRNA and GRIM-19 carried by attenuated Salmonella suppresses tumor cell growth

Liu

Zhang²,

Guo³

et al. 2012

Asian J Androl

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Persistent activation of Survivin and its overexpression contribute to the formation, progression and metastasis of several different tumor types. Therefore, Survivin is an ideal target for RNA interference mediated-growth inhibition. Blockade of Survivin using specific short hairpin RNAs (shRNA) can significantly reduce prostate tumor growth. RNA interference does not fully ablate target gene expression, owing to the idiosyncrasies associated with shRNAs and their targets. To enhance the therapeutic efficacy of Survivin-specific shRNA, we employed a combinatorial expression of Survivin-specific shRNA and gene associated with retinoid-interferon-induced mortality-19 (GRIM-19). Then, the GRIM-19 coding sequences and Survivin-specific shRNAs were used to create a dual expression plasmid vector and were carried by an attenuated strain of Salmonella enteric serovar typhimurium (S. typhimurium) to treat prostate cancer in vitro and in vivo. We found that the co-expressed Survivin-specific shRNA and GRIM-19 synergistically and more effectively inhibited prostate tumor proliferation and survival, when compared with treatment with either single agent alone in vitro and in vivo. This study has provided a novel cancer gene therapeutic approach for prostate cancer.

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Curcumin Inhibits Constitutive STAT3 Phosphorylation in Human Pancreatic Cancer Cell lines and Downregulation of Survivin/BIRC5 Gene Expression

Cited by 102 publications

References 21 publications

Stat3 promotes invasion of esophageal squamous cell carcinoma through up-regulation of MMP2

Stat3 promotes invasion of esophageal squamous cell carcinoma through up-regulation of MMP2

Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension

Plasmid-based Survivin shRNA and GRIM-19 carried by attenuated Salmonella suppresses tumor cell growth

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