Stat3 Promotes Metastatic Progression of Prostate Cancer

Abdulghani, Junaid; Gu, Lei; Dagvadorj, Ayush; Lutz, Jacqueline; Leiby, Benjamin E.; Bonuccelli, Gloria; Lisanti, Michael P.; Zellweger, Tobias; Alanen, Kalle; Mirtti, Tuomas; Visakorpi, Tapio; Bubendorf, Lukas; Nevalainen, Marja T.

doi:10.2353/ajpath.2008.071054

Cited by 215 publications

(184 citation statements)

References 43 publications

(46 reference statements)

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“…Recent studies have also linked Stat3 to metastatic progression in several different cancers, including prostate, lung, ovary, and gastrointestinal tract (16,18,(20)(21)(22). The influence of Stat3 on the metastatic potential of these cancers occurs through a variety of molecular mechanisms (35,(38)(39)(40). This study investigated the immunohistochemical staining of pStat3 in tissue samples of 70 patients with chordoma and sought to establish a relationship between expression and outcome.…”

Section: Discussionmentioning

confidence: 99%

A novel target for treatment of chordoma: signal transducers and activators of transcription 3

Yang

Schwab

Schoenfeld

et al. 2009

Molecular Cancer Therapeutics

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A major obstacle in the effective treatment of chordoma is that there are no identifiable biomarkers capable of predicting prognosis. Recent research has indicated that signal transducers and activators of transcription (Stat3) may be an important prognostic marker in some cancers, but its role in chordoma tumors has not been elucidated. In this study, the expression of Stat3 was evaluated in chordoma tissue microarray that contains 70 chordoma samples. Cells in the tissue microarray showed nuclear staining for phosphorylated Stat3 in all instances. The level of phosphorylated Stat3 expression correlated with the survival and severity of the disease. Three chordoma cell lines were exposed to SD-1029, a novel inhibitor of Stat3 activation. MTT assay showed that the growth of all chordoma cell lines was inhibited by SD-1029. The expression of Stat3 signaling cascade was inhibited in all chordoma cell lines after treatment with SD-1029. The cytotoxicity of the combination of SD-1029 and chemotherapeutic drugs is significantly better than either agent alone. Phosphorylation of Stat3 in chordoma cells in vitro and cellular proliferation in three-dimensional culture were inhibited by SD-1029. In conclusion, the Stat3 pathway is constitutively activated in chordomas and the level of expression may serve as a predictor for prognosis. Blockade of the Stat3 pathway represents a potential strategy for future treatment.

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Section: Discussionmentioning

confidence: 99%

A novel target for treatment of chordoma: signal transducers and activators of transcription 3

Yang

Schwab

Schoenfeld

et al. 2009

Molecular Cancer Therapeutics

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“…44,65 Fibronectin Cell Adhesion Assay PC cells were plated (5 Â 10 4 cells per well) on 96-well plates (Linbro/Titertek; MP Biomedicals, Solon, OH) coated with 7 mg/mL fibronectin (BD Biosciences) or 1 mg/mL of poly-Llysine (Ctrl; Sigma-Aldrich), incubated for 1 hour, fixed with 4% paraformaldehyde, and stained with crystal violet. This was followed by quantification of cell adhesion by a fluorescence plate reader (595 nm; POLARstar OPTIMA; BMG Labtech, Ortenberg, Germany) from three parallel wells.…”

Section: Boyden Chamber Migration Assaymentioning

confidence: 99%

“…Immunohistochemical staining of xenograft tumors and clinical human PCs grown as ex vivo organ cultures was performed as described previously, 39,43,45,47,65 and primary antibodies used are listed in Table 2. Sections of CWR22Pc and CWR22Rv1 cell pellets, fixed with 10% formalin and paraffin embedded, were immunostained for Twist1 and BMI1 by immunofluorescence cytochemistry.…”

Section: Immunostaining Of Paraffin-embedded Tissue Sections and Cellmentioning

confidence: 99%

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Talati

Ellsworth

et al. 2015

The American Journal of Pathology

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Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo, and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/beinduced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stemlike properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo. In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells. Most prostate cancer (PC)erelated deaths are because of development of metastatic disease. A central process in metastatic dissemination of PC is epithelial-to-mesenchymal transition (EMT), during which cancer cells attain more motile and invasive properties, invade through the basement membrane, and survive in systemic circulation. 1e3 Extravasation at distant organ sites is followed by adhesion of cancer cells to extracellular matrix proteins, such as fibronectin, 4e6 leading to formation of premetastatic niches and subsequent formation of macroscopic metastases. 7e9 Hallmarks of EMT in PC include disruption of adherens junctions through down-regulation of E-cadherin, 2 concomitant with a development of a migratory phenotype and up-regulation of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin. 10,11 Loss of E-cadherin results from mutations, DNA methylation, or silencing of E-cadherin promoter

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“…This in turn leads to the activation of STAT3 by phosphorylation of Tyr705 and subsequent translocation to the nucleus, where it can bind DNA and act as a transcription factor (11,12). Activated STAT3 has been found in primary as well as in metastatic prostate cancer and correlates with Gleason score, tumor stage, and castration resistance (11,13).…”

Section: Introductionmentioning

confidence: 99%

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Handle

Erb

Luef

et al. 2016

Molecular Cancer Research

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The proinflammatory cytokine IL6 is associated with bad prognosis in prostate cancer and implicated in progression to castration resistance. Suppressor of cytokine signaling 3 (SOCS3) is an IL6-induced negative feedback regulator of the IL6/Janus kinase (JAK)/STAT3 pathway. This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor-positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor-mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced androgen receptor activity after 3 weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly upregulated by the long-term treatment, and modulation of SOCS3 expression was sufficient to counteract this effect. These findings prove that SOCS3 plays an important role during anti-androgen treatment in an inflammatory environment.Implications: SOCS3 is frequently inactivated by promoter hypermethylation in prostate cancer, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines.

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Stat3 Promotes Metastatic Progression of Prostate Cancer

Cited by 215 publications

References 43 publications

A novel target for treatment of chordoma: signal transducers and activators of transcription 3

A novel target for treatment of chordoma: signal transducers and activators of transcription 3

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

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