Hypoxia increases androgen receptor activity in prostate cancer cells

Soo Yeon Park, Yun Jeong Kim, Allen C. Gao, James L. Mohler, Sergio A. Onate, Alejandro A. Hidalgo, Clement Ip, Eun Mi Park, Sun Young Yoon, Young Mee Park

Resultado de la investigación: Article

57 Citas (Scopus)

Resumen

Recent studies show that prostate cancer cells are able to survive in a hypoxic tumor environment, and the extent of tumor hypoxia correlates with poor clinical outcome. Androgen deprivation, the most common form of prostate cancer therapy, was itself shown to induce a state of transient hypoxia at the microenvironmental level. Because androgen receptor (AR) signaling plays a critical role in prostate cancer, we investigated the effect of hypoxia in regulating AR function. We found that in LNCaP prostate cancer cells, AR binding to the androgen-responsive element (ARE), prostate-specific antigen accumulation, and ARE-reporter gene activity were increased after hypoxia treatment. Hypoxia-enhanced AR function was also observed when AR was exogenously introduced into AR-null DU145 cells. Confocal microscopy and chromatin immunoprecipitation assays showed that AR translocation to the nucleus and AR recruitment to the prostate-specific antigen promoter were facilitated after hypoxia treatment. The AR stimulatory effect seemed to be ligand-dependent because it was abrogated when cells were cultured in an androgen-depleted medium, but was restored with the addition of R1881, a synthetic androgen. The sensitivity of AR activation to R1881 was also increased after hypoxia treatment. Although concentrations of <1 nmol/L R1881 did not induce ARE reporter activity under normoxic conditions, exposure to hypoxia greatly potentiated the AR response to low levels of R1881. Collectively, our results provide compelling evidence that changes in hypoxia/reoxygenation stimulate AR trans-activation and sensitization. The AR-stimulatory effect of an unstable tissue oxygenation milieu of a tumor is likely to contribute to treatment resistance and the emergence of recurrent prostate cancer.

Idioma originalEnglish
Páginas (desde-hasta)5121-5129
Número de páginas9
PublicaciónCancer Research
Volumen66
N.º10
DOI
EstadoPublished - 15 may 2006

Huella dactilar

Androgen Receptors
Prostatic Neoplasms
Androgens
Metribolone
Prostate-Specific Antigen
Hypoxia
Testosterone Congeners
Null Lymphocytes
Chromatin Immunoprecipitation
Reporter Genes
Confocal Microscopy
Cultured Cells
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Citar esto

Park, S. Y., Kim, Y. J., Gao, A. C., Mohler, J. L., Onate, S. A., Hidalgo, A. A., ... Park, Y. M. (2006). Hypoxia increases androgen receptor activity in prostate cancer cells. Cancer Research, 66(10), 5121-5129. https://doi.org/10.1158/0008-5472.CAN-05-1341
Park, Soo Yeon ; Kim, Yun Jeong ; Gao, Allen C. ; Mohler, James L. ; Onate, Sergio A. ; Hidalgo, Alejandro A. ; Ip, Clement ; Park, Eun Mi ; Yoon, Sun Young ; Park, Young Mee. / Hypoxia increases androgen receptor activity in prostate cancer cells. En: Cancer Research. 2006 ; Vol. 66, N.º 10. pp. 5121-5129.
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title = "Hypoxia increases androgen receptor activity in prostate cancer cells",
abstract = "Recent studies show that prostate cancer cells are able to survive in a hypoxic tumor environment, and the extent of tumor hypoxia correlates with poor clinical outcome. Androgen deprivation, the most common form of prostate cancer therapy, was itself shown to induce a state of transient hypoxia at the microenvironmental level. Because androgen receptor (AR) signaling plays a critical role in prostate cancer, we investigated the effect of hypoxia in regulating AR function. We found that in LNCaP prostate cancer cells, AR binding to the androgen-responsive element (ARE), prostate-specific antigen accumulation, and ARE-reporter gene activity were increased after hypoxia treatment. Hypoxia-enhanced AR function was also observed when AR was exogenously introduced into AR-null DU145 cells. Confocal microscopy and chromatin immunoprecipitation assays showed that AR translocation to the nucleus and AR recruitment to the prostate-specific antigen promoter were facilitated after hypoxia treatment. The AR stimulatory effect seemed to be ligand-dependent because it was abrogated when cells were cultured in an androgen-depleted medium, but was restored with the addition of R1881, a synthetic androgen. The sensitivity of AR activation to R1881 was also increased after hypoxia treatment. Although concentrations of <1 nmol/L R1881 did not induce ARE reporter activity under normoxic conditions, exposure to hypoxia greatly potentiated the AR response to low levels of R1881. Collectively, our results provide compelling evidence that changes in hypoxia/reoxygenation stimulate AR trans-activation and sensitization. The AR-stimulatory effect of an unstable tissue oxygenation milieu of a tumor is likely to contribute to treatment resistance and the emergence of recurrent prostate cancer.",
author = "Park, {Soo Yeon} and Kim, {Yun Jeong} and Gao, {Allen C.} and Mohler, {James L.} and Onate, {Sergio A.} and Hidalgo, {Alejandro A.} and Clement Ip and Park, {Eun Mi} and Yoon, {Sun Young} and Park, {Young Mee}",
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Park, SY, Kim, YJ, Gao, AC, Mohler, JL, Onate, SA, Hidalgo, AA, Ip, C, Park, EM, Yoon, SY & Park, YM 2006, 'Hypoxia increases androgen receptor activity in prostate cancer cells', Cancer Research, vol. 66, n.º 10, pp. 5121-5129. https://doi.org/10.1158/0008-5472.CAN-05-1341

Hypoxia increases androgen receptor activity in prostate cancer cells. / Park, Soo Yeon; Kim, Yun Jeong; Gao, Allen C.; Mohler, James L.; Onate, Sergio A.; Hidalgo, Alejandro A.; Ip, Clement; Park, Eun Mi; Yoon, Sun Young; Park, Young Mee.

En: Cancer Research, Vol. 66, N.º 10, 15.05.2006, p. 5121-5129.

Resultado de la investigación: Article

TY - JOUR

T1 - Hypoxia increases androgen receptor activity in prostate cancer cells

AU - Park, Soo Yeon

AU - Kim, Yun Jeong

AU - Gao, Allen C.

AU - Mohler, James L.

AU - Onate, Sergio A.

AU - Hidalgo, Alejandro A.

AU - Ip, Clement

AU - Park, Eun Mi

AU - Yoon, Sun Young

AU - Park, Young Mee

PY - 2006/5/15

Y1 - 2006/5/15

N2 - Recent studies show that prostate cancer cells are able to survive in a hypoxic tumor environment, and the extent of tumor hypoxia correlates with poor clinical outcome. Androgen deprivation, the most common form of prostate cancer therapy, was itself shown to induce a state of transient hypoxia at the microenvironmental level. Because androgen receptor (AR) signaling plays a critical role in prostate cancer, we investigated the effect of hypoxia in regulating AR function. We found that in LNCaP prostate cancer cells, AR binding to the androgen-responsive element (ARE), prostate-specific antigen accumulation, and ARE-reporter gene activity were increased after hypoxia treatment. Hypoxia-enhanced AR function was also observed when AR was exogenously introduced into AR-null DU145 cells. Confocal microscopy and chromatin immunoprecipitation assays showed that AR translocation to the nucleus and AR recruitment to the prostate-specific antigen promoter were facilitated after hypoxia treatment. The AR stimulatory effect seemed to be ligand-dependent because it was abrogated when cells were cultured in an androgen-depleted medium, but was restored with the addition of R1881, a synthetic androgen. The sensitivity of AR activation to R1881 was also increased after hypoxia treatment. Although concentrations of <1 nmol/L R1881 did not induce ARE reporter activity under normoxic conditions, exposure to hypoxia greatly potentiated the AR response to low levels of R1881. Collectively, our results provide compelling evidence that changes in hypoxia/reoxygenation stimulate AR trans-activation and sensitization. The AR-stimulatory effect of an unstable tissue oxygenation milieu of a tumor is likely to contribute to treatment resistance and the emergence of recurrent prostate cancer.

AB - Recent studies show that prostate cancer cells are able to survive in a hypoxic tumor environment, and the extent of tumor hypoxia correlates with poor clinical outcome. Androgen deprivation, the most common form of prostate cancer therapy, was itself shown to induce a state of transient hypoxia at the microenvironmental level. Because androgen receptor (AR) signaling plays a critical role in prostate cancer, we investigated the effect of hypoxia in regulating AR function. We found that in LNCaP prostate cancer cells, AR binding to the androgen-responsive element (ARE), prostate-specific antigen accumulation, and ARE-reporter gene activity were increased after hypoxia treatment. Hypoxia-enhanced AR function was also observed when AR was exogenously introduced into AR-null DU145 cells. Confocal microscopy and chromatin immunoprecipitation assays showed that AR translocation to the nucleus and AR recruitment to the prostate-specific antigen promoter were facilitated after hypoxia treatment. The AR stimulatory effect seemed to be ligand-dependent because it was abrogated when cells were cultured in an androgen-depleted medium, but was restored with the addition of R1881, a synthetic androgen. The sensitivity of AR activation to R1881 was also increased after hypoxia treatment. Although concentrations of <1 nmol/L R1881 did not induce ARE reporter activity under normoxic conditions, exposure to hypoxia greatly potentiated the AR response to low levels of R1881. Collectively, our results provide compelling evidence that changes in hypoxia/reoxygenation stimulate AR trans-activation and sensitization. The AR-stimulatory effect of an unstable tissue oxygenation milieu of a tumor is likely to contribute to treatment resistance and the emergence of recurrent prostate cancer.

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