Inappropriate activation of the androgen receptor by nonsteroids: Involvement of the Src kinase pathway and its therapeutic implications

Sonal J. Desai, Ai Hong Ma, Clifford G Tepper, Hongwu Chen, Hsing-Jien Kung

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The inappropriate activation of androgen receptor (AR) by nonsteroids is considered a potential mechanism in the emergence of hormone-refractory prostate tumors, but little is known about the properties of these " pseudoactivated" AR. Here, we present the first comprehensive analysis closely examining the properties of AR activated by the neuropeptide bombesin that distinguish it from androgen-activated AR. We show that bombesin-activated AR (a) is required for bombesin-induced growth of LNCaP cells, (b) has a transcriptional profile overlapping with, but not identical to, androgen-activated AR, (c) activates prostate-specific antigen by preferentially binding to its proximal promoter, and (d) assembles a distinct coactivator complex. Significantly, we found that Src kinase is critical for bombesin-induced AR-mediated activity and is required for translocation and transactivation of AR. Additionally, we identify c-Myc, a Src target gene, to be activated by bombesin and a potential coactivator of AR-mediated activity specific to bombesin-induced signaling. Because Src kinase is often activated by other nonsteroids, such as other neuropeptides, growth factors, chemokines, and cytokines, our findings have general applicability and provide rationale for investigating the efficacy of the Src kinase pathway as a target for the prevention of relapsed prostate cancers.

Original languageEnglish (US)
Pages (from-to)10449-10459
Number of pages11
JournalCancer Research
Volume66
Issue number21
DOIs
StatePublished - Nov 1 2006

Fingerprint

src-Family Kinases
Androgen Receptors
Bombesin
Therapeutics
Neuropeptides
Androgens
src Genes
Prostate-Specific Antigen
Chemokines
Transcriptional Activation
Prostate
Prostatic Neoplasms
Intercellular Signaling Peptides and Proteins
Hormones
Cytokines

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inappropriate activation of the androgen receptor by nonsteroids : Involvement of the Src kinase pathway and its therapeutic implications. / Desai, Sonal J.; Ma, Ai Hong; Tepper, Clifford G; Chen, Hongwu; Kung, Hsing-Jien.

In: Cancer Research, Vol. 66, No. 21, 01.11.2006, p. 10449-10459.

Research output: Contribution to journalArticle

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