Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor in androgen-dependent but not castrate-resistant prostate cancer cells

Liqun Chen, Salma Siddiqui, Swagata Bose, Benjamin Mooso, Alfredo Asuncion, Roble G. Bedolla, Ruth Louise Vinall, Clifford G Tepper, Regina F Gandour-Edwards, XuBao Shi, Xiao Hua Lu, Javed Siddiqui, Arul M. Chinnaiyan, Rohit Mehra, Ralph W deVere White, Kermit L Carraway, Paramita M Ghosh

Research output: Contribution to journalArticle

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Abstract

Patients with advanced prostate cancer (PCa) are initially susceptible to androgen withdrawal (AW), but ultimately develop resistance to this therapy (castration-resistant PCa, CRPC). Here, we show that AW can promote CRPC development by increasing the levels of the receptor tyrosine kinase ErbB3 in androgen-dependent PCa, resulting in AW-resistant cell cycle progression and increased androgen receptor (AR) transcriptional activity. CRPC cell lines and human PCa tissue overexpressed ErbB3, whereas downregulation of ErbB3 prevented CRPC cell growth. Investigation of the mechanism by which AW augments ErbB3, using normal prostate-derived pRNS-1-1 cells, and androgen-dependent PCa lines LNCaP, PC346C, and CWR22 mouse xenografts, revealed that the AR suppresses ErbB3 protein levels, whereas AW relieves this suppression, showing for the first time the negative regulation of ErbB3 by AR. We show that AR activation promotes ErbB3 degradation in androgen-dependent cells, and that this effect is mediated by AR-dependent transcriptional upregulation of neuregulin receptor degradation protein-1 (Nrdp1), an E3 ubiquitin ligase that targets ErbB3 for degradation but whose role in PCa has not been previously examined. Therefore, AW decreases Nrdp1 expression, promoting ErbB3 protein accumulation, and leading to AR-independent proliferation. However, in CRPC sublines of LNCaP and CWR22, which strongly overexpress the AR, ErbB3 levels remain elevated due to constitutive suppression of Nrdp1, which prevents AR regulation of Nrdp1. Our observations point to a model of CRPC development in which progression of PCa to castration resistance is associated with the inability of AR to transcriptionally regulate Nrdp1, and predict that inhibition of ErbB3 during AW may impair CRPC development.

Original languageEnglish (US)
Pages (from-to)5994-6003
Number of pages10
JournalCancer Research
Volume70
Issue number14
DOIs
StatePublished - Jul 15 2010

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Neuregulins
Androgen Receptors
Androgens
Proteolysis
Castration
Prostatic Neoplasms
Ubiquitin-Protein Ligases
Receptor Protein-Tyrosine Kinases
Heterografts
Prostate
Cell Cycle
Proteins
Up-Regulation
Down-Regulation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor in androgen-dependent but not castrate-resistant prostate cancer cells. / Chen, Liqun; Siddiqui, Salma; Bose, Swagata; Mooso, Benjamin; Asuncion, Alfredo; Bedolla, Roble G.; Vinall, Ruth Louise; Tepper, Clifford G; Gandour-Edwards, Regina F; Shi, XuBao; Lu, Xiao Hua; Siddiqui, Javed; Chinnaiyan, Arul M.; Mehra, Rohit; deVere White, Ralph W; Carraway, Kermit L; Ghosh, Paramita M.

In: Cancer Research, Vol. 70, No. 14, 15.07.2010, p. 5994-6003.

Research output: Contribution to journalArticle

Chen, L, Siddiqui, S, Bose, S, Mooso, B, Asuncion, A, Bedolla, RG, Vinall, RL, Tepper, CG, Gandour-Edwards, RF, Shi, X, Lu, XH, Siddiqui, J, Chinnaiyan, AM, Mehra, R, deVere White, RW, Carraway, KL & Ghosh, PM 2010, 'Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor in androgen-dependent but not castrate-resistant prostate cancer cells', Cancer Research, vol. 70, no. 14, pp. 5994-6003. https://doi.org/10.1158/0008-5472.CAN-09-4440
Chen, Liqun ; Siddiqui, Salma ; Bose, Swagata ; Mooso, Benjamin ; Asuncion, Alfredo ; Bedolla, Roble G. ; Vinall, Ruth Louise ; Tepper, Clifford G ; Gandour-Edwards, Regina F ; Shi, XuBao ; Lu, Xiao Hua ; Siddiqui, Javed ; Chinnaiyan, Arul M. ; Mehra, Rohit ; deVere White, Ralph W ; Carraway, Kermit L ; Ghosh, Paramita M. / Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor in androgen-dependent but not castrate-resistant prostate cancer cells. In: Cancer Research. 2010 ; Vol. 70, No. 14. pp. 5994-6003.
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AU - Bose, Swagata

AU - Mooso, Benjamin

AU - Asuncion, Alfredo

AU - Bedolla, Roble G.

AU - Vinall, Ruth Louise

AU - Tepper, Clifford G

AU - Gandour-Edwards, Regina F

AU - Shi, XuBao

AU - Lu, Xiao Hua

AU - Siddiqui, Javed

AU - Chinnaiyan, Arul M.

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