Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of ser727 on STAT3 in prostate cancer cells

Fu Ning Hsu, Mei Chih Chen, Kuan Chia Lin, Yu Ting Peng, Pei Chi Li, Eugene Lin, Ming Ching Chiang, Jer Tsong Hsieh, Ho Lin

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Cyclin-dependent kinase 5 (Cdk5) is known to regulate prostate cancer metastasis. Our previous results indicated that Cdk5 activates androgen receptor (AR) and supports prostate cancer growth. We also found that STAT3 is a target of Cdk5 in promoting thyroid cancer cell growth, whereas STAT3 may play a role as a regulator to AR activation under cytokine control. In this study, we investigated the regulation of Cdk5 and its activator p35 on STAT3/AR signaling in prostate cancer cells. Our results show that Cdk5 biochemically interacts with STAT3 and that this interaction depends on Cdk5 activation in prostate cancer cells. The phosphorylation of STAT3 at Ser727 (p-Ser727-STAT3) is regulated by Cdk5 in cells and xenograft tumors. The mutant of STAT3 S727A reduces its interaction with Cdk5. We further show that the nuclear distribution of p-Ser727- STAT3 and the expression of STAT3-regulated genes (junB, c-fos, c-myc, and survivin) are regulated by Cdk5 activation. STAT3 mutant does not further decrease cell proliferation upon Cdk5 inhibition, which implies that the role of STAT3 regulated by Cdk5 correlates to cell proliferation control. Interestingly, Cdk5 may regulate the interaction between STAT3 and AR through phosphorylation of Ser727- STAT3 and therefore upregulate AR protein stability and transactivation. Correspondingly, clinical evidence shows that the level of p-Ser727-STAT3 is significantly correlated with Gleason score and the levels of upstream regulators (Cdk5 and p35) as well as downstream protein (AR). In conclusion, this study demonstrates that Cdk5 regulates STAT3 activation through Ser727 phosphorylation and further promotes AR activation by protein-protein interaction in prostate cancer cells.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume305
Issue number8
DOIs
StatePublished - Oct 15 2013

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Cyclin-Dependent Kinase 5
Androgen Receptors
Prostatic Neoplasms
Phosphorylation
Cell Proliferation
fos Genes
Proteins
Neoplasm Grading
Protein Stability

Keywords

  • Androgen receptor
  • Cyclin-dependent kinase 5
  • Phosphorylation
  • Prostate cancer
  • Signal transducer and activator of transcription 3

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of ser727 on STAT3 in prostate cancer cells. / Hsu, Fu Ning; Chen, Mei Chih; Lin, Kuan Chia; Peng, Yu Ting; Li, Pei Chi; Lin, Eugene; Chiang, Ming Ching; Hsieh, Jer Tsong; Lin, Ho.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 305, No. 8, 15.10.2013.

Research output: Contribution to journalArticle

Hsu, Fu Ning ; Chen, Mei Chih ; Lin, Kuan Chia ; Peng, Yu Ting ; Li, Pei Chi ; Lin, Eugene ; Chiang, Ming Ching ; Hsieh, Jer Tsong ; Lin, Ho. / Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of ser727 on STAT3 in prostate cancer cells. In: American Journal of Physiology - Endocrinology and Metabolism. 2013 ; Vol. 305, No. 8.
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AU - Hsu, Fu Ning

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AU - Peng, Yu Ting

AU - Li, Pei Chi

AU - Lin, Eugene

AU - Chiang, Ming Ching

AU - Hsieh, Jer Tsong

AU - Lin, Ho

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AB - Cyclin-dependent kinase 5 (Cdk5) is known to regulate prostate cancer metastasis. Our previous results indicated that Cdk5 activates androgen receptor (AR) and supports prostate cancer growth. We also found that STAT3 is a target of Cdk5 in promoting thyroid cancer cell growth, whereas STAT3 may play a role as a regulator to AR activation under cytokine control. In this study, we investigated the regulation of Cdk5 and its activator p35 on STAT3/AR signaling in prostate cancer cells. Our results show that Cdk5 biochemically interacts with STAT3 and that this interaction depends on Cdk5 activation in prostate cancer cells. The phosphorylation of STAT3 at Ser727 (p-Ser727-STAT3) is regulated by Cdk5 in cells and xenograft tumors. The mutant of STAT3 S727A reduces its interaction with Cdk5. We further show that the nuclear distribution of p-Ser727- STAT3 and the expression of STAT3-regulated genes (junB, c-fos, c-myc, and survivin) are regulated by Cdk5 activation. STAT3 mutant does not further decrease cell proliferation upon Cdk5 inhibition, which implies that the role of STAT3 regulated by Cdk5 correlates to cell proliferation control. Interestingly, Cdk5 may regulate the interaction between STAT3 and AR through phosphorylation of Ser727- STAT3 and therefore upregulate AR protein stability and transactivation. Correspondingly, clinical evidence shows that the level of p-Ser727-STAT3 is significantly correlated with Gleason score and the levels of upstream regulators (Cdk5 and p35) as well as downstream protein (AR). In conclusion, this study demonstrates that Cdk5 regulates STAT3 activation through Ser727 phosphorylation and further promotes AR activation by protein-protein interaction in prostate cancer cells.

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