Overexpression of Cdc25B, an androgen receptor coactivator, in prostate cancer

Ngan, Elly Sau-Wai; Hashimoto, Yoshihiro; Ma, Zhiqing; Tsai, Ming‐Jer; Tsai, Sophia Y.

doi:10.1038/sj.onc.1206121

Cited by 115 publications

(85 citation statements)

References 13 publications

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“…Interestingly, we have found that the most highly overexpressed cell-cycle-regulatory genes in androgen-independent PCa are Cdk1, cyclin B1, and cyclin B2 (3.3, 2.7, and 2.6-fold increases in median expression, respectively), with the cyclin B1 increase being statistically significant (6). Previous studies have also found increased expression of cyclin B1 and Cdc25 in PCa, and this has been associated with more aggressive PCa and progression to androgen-independent PCa (39)(40)(41). Based on these observations, we examined androgen-independent PCa cells to determine whether Cdk1 may mediate enhanced responses to low levels of androgen.…”

Section: Roscovitine Abrogates Ar Stabilization At Low Androgen Levelmentioning

confidence: 77%

Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1

Chen

Yuan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

185

203

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Androgen receptors (ARs) are phosphorylated at multiple sites in response to ligand binding, but the kinases mediating AR phosphorylation and the importance of these kinases in AR function have not been established. Here we show that cyclin-dependent kinase 1 (Cdk1) mediates AR phosphorylation at Ser-81 and increases AR protein expression, and that Cdk1 inhibitors decrease AR Ser-81 phosphorylation, protein expression, and transcriptional activity in prostate cancer (PCa) cells. The decline in AR protein expression mediated by the Cdk inhibitor roscovitine was prevented by proteosome inhibitors, indicating that Cdk1 stabilizes AR protein, although roscovitine also decreased AR message levels. Analysis of an S81A AR mutant demonstrated that this site is not required for transcriptional activity or Cdk1-mediated AR stabilization in transfected cells. The AR is active and seems to be stabilized by low levels of androgen in ''androgen-independent'' PCas that relapse subsequent to androgen-deprivation therapy. Significantly, the expression of cyclin B and Cdk1 was increased in these tumors, and treatment with roscovitine abrogated responses to low levels of androgen in the androgen-independent C4-2 PCa cell line. Taken together, these findings identify Cdk1 as a Ser-81 kinase and indicate that Cdk1 stabilizes AR protein by phosphorylation at a site(s) distinct from Ser-81. Moreover, these results indicate that increased Cdk1 activity is a mechanism for increasing AR expression and stability in response to low androgen levels in androgen-independent PCas, and that Cdk1 antagonists may enhance responses to androgen-deprivation therapy.

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Section: Roscovitine Abrogates Ar Stabilization At Low Androgen Levelmentioning

confidence: 77%

Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1

Chen

Yuan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

185

203

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“…(46,47) The presence of DAX-1 in endometrial hyperplasia may therefore represent an in situ defensive mechanism for modulating unopposed estrogenic effects by acting as a corepressor for ER as proposed in human prostatic lesions. (25,26,48) There was a significant inverse correlation between DAX-1 immunoreactivity and histological grade of carcinoma. These findings also suggest that DAX-1 may inhibit cell proliferation and the progression of endometrial carcinoma in a manner similar to endometrial hyperplasia described earlier.…”

Section: Discussionmentioning

confidence: 91%

Orphan nuclear receptor DAX‐1 in human endometrium and its disorders

Saito¹,

Itō²,

Suzuki³

et al. 2005

Cancer Science

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DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family. DAX-1 functions as a global negative regulator of steroid hormone production. It inhibits adrenal 4 binding protein (Ad4BP)/steroidogenic factor-1 (SF-1) pathway-dependent P450arom expression in cultured human endometriotic stromal cells and acts as a corepressor for estrogen receptors (ER). In this study we first examined the localization of DAX-1 in 46 normal cycling endometria, 36 cases of endometrial hyperplasia and 103 cases of endometrial carcinoma by using immunohistochemistry to elucidate the possible involvement of DAX-1 and its correlation to the status of Ad4BP/SF-1, a universal transcription factor of steroidogenesis. We then evaluated DAX-1 mRNA expression, using quantitative reverse transcription-polymerase chain reaction for DAX-1 in 33 cases of endometrial carcinoma for further characterization. We subsequently correlated these findings with various clinicopathological parameters of the cases. Ad4BP/SF-1 immunoreactivity was not detected in any human endometria examined. A significant inverse correlation was detected between the status of DAX-1 immunoreactivity and histological grade (P = 0.0003) in endometrial carcinoma. The labeling index (LI) values of DAX-1 in normal endometrium during the secretory phase (P < 0.0001) and hyperplasia (P < 0.0001) were significantly higher than that of carcinoma. No significant correlations were detected between DAX-1 immunoreactivity and amounts of aromatase mRNA. There was a statistically significant positive correlation between DAX-1 and ERα α α α (P = 0.006) and ERβ β β β LI (P < 0.001). These findings suggest that DAX-1 may inhibit the proliferation and progression of endometrial carcinoma through inhibition of estrogenic actions, possibly by interacting with ER present in carcinoma cells, rather than regulating in situ steroidogenesis. (Cancer Sci 2005; 96: 645-652) E ndometrial carcinoma is one of the most common pelvic malignancies among women worldwide, and its incidence has recently increased.(1,2) In situ estrogen metabolism, including synthesis and degradation, has been recently recognized as a very important factor in the development and progression of various human estrogen-dependent neoplasms, including endometrial carcinoma, especially the endometrioid type. (3,4) In endometrial carcinoma, in situ 17β-estradiol (E2) availability has been reported to be closely associated with the pathogenesis and development of endometrial proliferative disorders including endometrial hyperplasia and carcinoma, especially the endometrioid type.(5) DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1) is a recently characterized member of the orphan nuclear receptor family.(6,7) DAX-1 is expressed in the adrenal cortex, ovary, Leydig cells and other endocrine cells such as testicular Sertoli cells, pituitary gonadotropes, vent...

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“…Overexpression of CDC25A and CDC25B has been documented in many human malignancies, suggesting their involvement in the pathogenesis and progression of malignant transformation (Gasparotto et al, 1997;Kudo et al, 1997;Hernandez et al, 2000Hernandez et al, , 2001Ito et al, 2002;Miyata et al, 2001;Sasaki et al, 2001;Sato et al, 2001;Ngan et al, 2003). PDAC is characterized by uncontrolled cell-cycle progression, resistance to cell-cycle arrest and apoptosis, in part due to alterations involving mutations of the proto-oncogene K-ras and p53, Smad4/DPC4 and p16/CDKN2A tumor-suppressor gene mutations Bardeesy and DePinho, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…CDC25A and CDC25B, but not CDC25C, exhibit oncogenic potential since they can transform primary murine fibroblasts in cooperation with either activated H-ras or loss of RB1 (Galaktionov et al, 1995). Overexpression of CDC25A or CDC25B has been reported in different human tumors, including non-Hodgkin's lymphoma, neuroblastoma, head and neck cancer, lung cancer, esophageal cancer, gastric cancer, colorectal cancer and prostate cancer (Gasparotto et al, 1997;Kudo et al, 1997;Hernandez et al, 2000Hernandez et al, , 2001Miyata et al, 2001;Sasaki et al, 2001;Sato et al, 2001;Ito et al, 2002;Ngan et al, 2003). The expression and functional role of CDC25B phosphatases in PDAC has so far not been analysed.…”

Section: Introductionmentioning

confidence: 99%

Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma

Guo

Kleeff

et al. 2004

Oncogene

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Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Deregulation of cell-cycle control is thought to be a crucial event in malignant transformation, and CDC25 phosphatases are a family of cyclin-dependent kinase activators, which act at different points of the cell cycle, including G1-S and G2-M transition. Here, we investigated the expression and functional significance of CDC25s in PDAC. CDC25B mRNA expression levels in human pancreatic tissue samples were analysed by cDNA array, quantitative PCR and Northern blotting. Immunohistochemistry was carried out to localize and quantify CDC25B expression. Two specific CDC25B inhibitors were utilized to determine the functional relevance of CDC25B. By quantitative RT-PCR, CDC25B mRNA was overexpressed in pancreatic cancer (7.5-fold) in comparison to the normal pancreas. Strong nuclear CDC25B immunoreactivity was present in both pancreatic and metastatic cancer samples, and there was a marked increase of the percentage of positive cells in primary cancer (48.6716.3%) and metastatic tissues (71.773.1%) compared to normal samples (8.371.8%). Two CDC25B inhibitors reduced the growth of pancreatic cancer cell lines, resulting in the accumulation of phosphorylated CDC2 and G2/M arrest. These findings demonstrate an important role of CDC25B in cell-cycle progression, raising the possibility that inhibition of CDC25B may have therapeutic potential in pancreatic cancer.

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Overexpression of Cdc25B, an androgen receptor coactivator, in prostate cancer

Cited by 115 publications

References 13 publications

Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1

Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1

Orphan nuclear receptor DAX‐1 in human endometrium and its disorders

Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma

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