Endothelin-1 enhances the expression of the androgen receptor via activation of the c-myc pathway in prostate cancer cells

June G. Lee, Rong Zheng, Jennifer Marie McCafferty-Cepero, Kerry L. Burnstein, David M. Nanus, Ruoqian Shen

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Increasing evidence suggests that androgen independent prostate cancer (PC) maintains a functional androgen receptor (AR) pathway despite the low levels of circulating androgen following androgen withdrawal, the molecular mechanisms of which are not well defined yet. To address this question, we investigated the effects of endothelin-1 (ET-1) on AR expression. Western analysis and RT-PCR revealed that in the presence of ET-1, levels of AR significantly increased in a time- and dose-dependent manner in LNCaP cells. Pretreatments with inhibitors of Src and phosphoinositide kinase 3 (PI-3K) suppressed ET-1-induced AR expression. As ET-1 was reported to cause a transient increase in c-myc mRNA levels, we examined the involvement of c-myc in ET-1-mediated AR expression. Transient transfection of c-myc siRNA neutralized ET-1-induced AR expression, suggesting that AR induction by ET-1 is c-myc dependent. AR can regulate the transcription of its own gene via a mechanism in which c-myc plays a crucial role. Therefore, we assessed if ET-1-induced-c-myc leads to the enhancement of AR transcription. Reporter gene assays using the previously identified AR gene enhancer containing a c-myc binding site were conducted in LNCaP cells. We found that ET-1 induced reporter gene activity from the construct containing the wild-type but not mutant c-myc binding site. Chromatin immunoprecipitation assays confirmed that ET-1 increased interaction between c-myc and c-myc binding sites in AR enhancer, suggesting that ET-1-induced AR transcription occurs via c-myc-mediated AR transcription. Together, these data support the notion that ET-1, via Src/PI-3K signaling, augments c-myc expression leading to enhanced AR expression in PC.

Original languageEnglish (US)
Pages (from-to)141-149
Number of pages9
JournalMolecular Carcinogenesis
Volume48
Issue number2
DOIs
StatePublished - Feb 1 2009

Keywords

  • Androgen receptor
  • C-myc
  • Endothelin-1
  • PI-3K
  • Prostate cancer
  • Src

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

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