Signal transducer and activator of transcription 5A/B in prostate and breast cancers

Tan, Shyh‐Han; Nevalainen, Marja T.

doi:10.1677/erc-08-0013

Cited by 98 publications

(102 citation statements)

References 223 publications

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“…Stat5 has been previously linked to PCa progression (31,32). Li and colleagues reported a strong positive correlation with Stat5 expression and high Gleason score in 114 human PCa (24).…”

Section: Discussionmentioning

confidence: 98%

Transcription Factor Stat5 Knockdown Enhances Androgen Receptor Degradation and Delays Castration-Resistant Prostate Cancer Progression In vivo

Thomas

Zoubeidi

Kuruma

et al. 2011

Molecular Cancer Therapeutics

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Signal transducer and activator of transcription 5 (Stat5) plays an important role in the transition of prostate cancer (PCa) to its castrate-resistant state. Pharmacologic targeting of Stat5 is a rational approach to delay castrate-resistant progression, in part, because Stat5 cooperates with the androgen receptor (AR) to promote PCa progression. Immunostaining of tissue microarrays was used to correlate Stat5 expression with Gleason grade and to characterize changes in treatment-naive and androgen-deprived human PCa. Potency of a Stat5 antisense oligonucleotide (ASO) on Stat5 knockdown, cell growth, and apoptosis was assessed in LNCaP, C4-2, and DU145 cells. Effects of Stat5 knockdown on AR activity and stability was assessed using a PSA transactivation-luciferase assay and cyclohexamide plus MG132 treatment, respectively. LNCaP tumorbearing mice were castrated and randomly assigned to treatment with Stat5-ASO or controls. Here, we show that the frequency of Stat5 expression is significantly increased in high Gleason grade as well as in hormone-treated PCa. Also, specific knockdown of Stat5 with ASO abrogates androgen-induced AR nuclear translocation and PSA transactivation despite R1881 stimulation. Moreover, Stat5 knockdown destabilizes AR, which leads to AR degradation via the proteasome. Shown for the first time as a preclinical proof-ofprinciple, Stat5 knockdown with Stat5-ASO significantly delays CRPC tumor progression in vivo. Thereby, we are able to recapitulate our in vitro results by reducing serum PSA and expression levels of target proteins in the xenograft tumors. Mol Cancer Ther; 10(2); 347-59. Ó2011 AACR.

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“…Stat5 has been previously linked to PCa progression (31,32). Li and colleagues reported a strong positive correlation with Stat5 expression and high Gleason score in 114 human PCa (24).…”

Section: Discussionmentioning

confidence: 98%

Transcription Factor Stat5 Knockdown Enhances Androgen Receptor Degradation and Delays Castration-Resistant Prostate Cancer Progression In vivo

Thomas

Zoubeidi

Kuruma

et al. 2011

Molecular Cancer Therapeutics

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“…As STAT3 has been the focus of cancer research, STAT3 inhibitors are being investigated, and a growing number of preclinical studies are ongoing. Therefore, more and more researchers have begun to focus on STAT5 (15)(16)(17)(18)(19). Evidence reveals that inhibition of STAT5 affects biological behavior of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

STAT5a-targeting miRNA enhances chemosensitivity to cisplatin and 5-fluorouracil in human colorectal cancer cells

et al. 2012

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Abstract. Signal transducers and activators of transcription 5 (STAT5) has been shown to be involved in a variety of cellular processes, including survival, proliferation, invasion, angiogenesis and immune evasion and is frequently overexpressed in human solid tumors and blood malignancies. The aim of this study was to investigate the role of STAT5a in colorectal cancer (CRC) progression. We inhibited the expression of STAT5a using lentivirus-mediated artificial microRNA (miRNA) interference in vitro and investigated the viability of CRC cells by CCK-8 assay. We observed the cell viability after treatment with cisplatin (CDDP) or 5-fluorouracil (5-Fu) by CCK-8 assay, and the apoptosis induced by chemotherapy using flow cytometric analysis and Annexin V RFP staining assay. We inhibited the mRNA expression by 54% and the protein expression by 60% of STAT5 by RNA interference targeting STAT5a. Cell viability assays showed that inhibition of STAT5a did not affect the viability of SW1116 cells. However, we found that inhibition of STAT5a restored the sensitivity of SW1116 cells to CDDP and 5-Fu. In additional experiments, we found that inhibition of STAT5a significantly promoted CRC cell apoptosis by CDDP and 5-Fu. In the present study, we found that inhibition of STAT5a promotes apoptosis of CRC cells induced by chemotherapy drugs, such as CDDP or 5-Fu. These results suggest that inhibition of STAT5a may serve as a potential new target for CRC treatment.

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“…STAT5A/B regulates the viability of prostate cancer cells and is activated in human prostate cancer cells (17). Patients with specific STAT3 phosphorylation had a different prognosis compared to patients without this STAT3 phosphorylation (18).…”

Section: Discussionmentioning

confidence: 99%

Sorbitol dehydrogenase expression is regulated by androgens in the human prostate

Szabò

Hämäläinen²,

Loikkanen³

et al. 2010

Oncol Rep

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Abstract.Sorbitol is an intermediate in the polyol pathway, which converts from glucose to fructose by sorbitol dehydrogenase (SORD). Androgens are essential for the development of prostate cancer. We studied castration-induced gene expression changes in the human prostate using the GeneChip array, and identified SORD as being androgen-regulated in the human prostate. A putative androgen-responsive regulatory region at the SORD 5' promoter was identified using promoter deletion constructs in a luciferase reporter assay in COS-7 cells. Chromatin immunoprecipitation assay was used to assess the binding of androgen receptor to suggested androgen responsive regulatory region. Finally, the expression of SORD in the human prostate was evaluated in 29 prostate tissue samples by immunohistochemistry. The expression of SORD decreased after castration. Androgen supplementation to the LNCaP prostate cancer cell line led to a 7.5-fold increase in SORD mRNA expression. Furthermore, a chromatin immunoprecipitation assay proved that the androgen receptor can bind to this putative androgen-responsive regulatory region. Finally, the expression of SORD in the human prostate was localised to epithelial cells of both benign and malignant prostate tissue by immunohistochemistry. In prostate cancer, increased immunostaining was associated with high Gleason patterns and high serum prostate-specific antigen concentrations. These results show that SORD is a novel androgen-regulated gene in the human prostate and suggest the need for more detailed analysis of the physiological role of SORD in the prostate.

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Signal transducer and activator of transcription 5A/B in prostate and breast cancers

Cited by 98 publications

References 223 publications

Transcription Factor Stat5 Knockdown Enhances Androgen Receptor Degradation and Delays Castration-Resistant Prostate Cancer Progression In vivo

Transcription Factor Stat5 Knockdown Enhances Androgen Receptor Degradation and Delays Castration-Resistant Prostate Cancer Progression In vivo

STAT5a-targeting miRNA enhances chemosensitivity to cisplatin and 5-fluorouracil in human colorectal cancer cells

Sorbitol dehydrogenase expression is regulated by androgens in the human prostate

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