Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells

Johanny Tonos De Leon; Aki Iwai; Clementine Feau; Yenni Garcia; Heather A. Balsiger; Cheryl L. Storer; Raquel M. Suro; Kristine M. Garza; Sunmin Lee; Yeong Sang Kim; Yu Chen; Yang Min Ning; Daniel L. Riggs; Robert J. Fletterick; R. Kiplin Guy; Jane B. Trepel; Leonard M. Neckers; Marc B. Cox

doi:10.1073/pnas.1105160108

Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells

Johanny Tonos De Leon, Aki Iwai, Clementine Feau, Yenni Garcia, Heather A. Balsiger, Cheryl L. Storer, Raquel M. Suro, Kristine M. Garza, Sunmin Lee, Yeong Sang Kim, Yu Chen, Yang Min Ning, Daniel L. Riggs, Robert J. Fletterick, R. Kiplin Guy, Jane B. Trepel, Leonard M. Neckers, Marc B. Cox

Research output: Contribution to journal › Article › peer-review

114 Scopus citations

Abstract

Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52- enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation.

Original language	English
Pages (from-to)	11878-11883
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	108
Issue number	29
DOIs	https://doi.org/10.1073/pnas.1105160108
State	Published - Jul 19 2011

Keywords

FKBP4
Immunophilin
Steroid hormone receptor

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1105160108

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De Leon, J. T., Iwai, A., Feau, C., Garcia, Y., Balsiger, H. A., Storer, C. L., Suro, R. M., Garza, K. M., Lee, S., Kim, Y. S., Chen, Y., Ning, Y. M., Riggs, D. L., Fletterick, R. J., Guy, R. K., Trepel, J. B., Neckers, L. M., & Cox, M. B. (2011). Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 108(29), 11878-11883. https://doi.org/10.1073/pnas.1105160108

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title = "Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells",

abstract = "Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52- enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation.",

keywords = "FKBP4, Immunophilin, Steroid hormone receptor",

author = "{De Leon}, {Johanny Tonos} and Aki Iwai and Clementine Feau and Yenni Garcia and Balsiger, {Heather A.} and Storer, {Cheryl L.} and Suro, {Raquel M.} and Garza, {Kristine M.} and Sunmin Lee and Kim, {Yeong Sang} and Yu Chen and Ning, {Yang Min} and Riggs, {Daniel L.} and Fletterick, {Robert J.} and Guy, {R. Kiplin} and Trepel, {Jane B.} and Neckers, {Leonard M.} and Cox, {Marc B.}",

year = "2011",

month = jul,

day = "19",

doi = "10.1073/pnas.1105160108",

language = "English",

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De Leon, JT, Iwai, A, Feau, C, Garcia, Y, Balsiger, HA, Storer, CL, Suro, RM, Garza, KM, Lee, S, Kim, YS, Chen, Y, Ning, YM, Riggs, DL, Fletterick, RJ, Guy, RK, Trepel, JB, Neckers, LM & Cox, MB 2011, 'Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 29, pp. 11878-11883. https://doi.org/10.1073/pnas.1105160108

Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells. / De Leon, Johanny Tonos; Iwai, Aki; Feau, Clementine et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 29, 19.07.2011, p. 11878-11883.

Research output: Contribution to journal › Article › peer-review

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T1 - Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells

AU - De Leon, Johanny Tonos

AU - Iwai, Aki

AU - Feau, Clementine

AU - Garcia, Yenni

AU - Balsiger, Heather A.

AU - Storer, Cheryl L.

AU - Suro, Raquel M.

AU - Garza, Kristine M.

AU - Lee, Sunmin

AU - Kim, Yeong Sang

AU - Chen, Yu

AU - Ning, Yang Min

AU - Riggs, Daniel L.

AU - Fletterick, Robert J.

AU - Guy, R. Kiplin

AU - Trepel, Jane B.

AU - Neckers, Leonard M.

AU - Cox, Marc B.

PY - 2011/7/19

Y1 - 2011/7/19

N2 - Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52- enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation.

AB - Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52- enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation.

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KW - Steroid hormone receptor

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AN - SCOPUS:79961042759

SN - 0027-8424

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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