Endothelin-1 Enhances the Expression of the Androgen Receptor Via Activation of the c-myc Pathway in Prostate Cancer Cells

Urologic Oncology Laboratory, Department of Urology, Weill Cornell Medical College, New York, NY 10021, USA.
Molecular Carcinogenesis (Impact Factor: 4.81). 02/2009; 48(2):141-9. DOI: 10.1002/mc.20462
Source: PubMed


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.

6 Reads
  • Source
    • "c-Myc may also be induced by certain stressors, such as ultraviolet radiation [49]. These transcription factors are shown to positively regulate AR transcription [50] [51] [52]. Also, CREB and Sp1 have been suggested to be involved in the oxidative stress signaling pathway [53] [54], as well as in regulating AR transcription [55] [56] [57]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aberrant androgen receptor (AR) signaling plays a critical role in androgen-dependent prostate cancer (PCa), as well as in castration-resistant PCa (CRPC). Oxidative stress seems to contribute to the tumorigenesis and progression of PCa, as well as the development of CRPC, via activation of AR signaling. This notion is supported by the fact that there is an aberrant or improper regulation of the redox status in these disorders. Additionally, androgen-deprivation-induced oxidative stress seems to be involved in the pathogenesis of several disorders caused by androgen-deprivation therapy (ADT), including osteoporosis, neurodegenerative disease, and cardiovascular disease. Oxidative stress can be suppressed with antioxidants or via a reduction in reactive oxygen species production. Thus, developing new therapeutic agents that reduce oxidative stress might be useful in preventing the conversion of androgen-dependent PCa into CRPC, as well as reducing the adverse effects associated with ADT. The objective of this review is to provide an overview regarding the relationship between oxidative stress and AR signaling in the context of PCa and especially CRPC. Additionally, we discuss the potential use of antioxidant therapies in the treatment of PCa.
    Full-text · Article · Jul 2011 · Free Radical Biology and Medicine
  • Source
    • "Recently, in a more definitive manner, Myc was proven to regulate AR transcription in LNCaP cells that express AR, and are the standard cell line used as a model for androgen-dependent PCa (Lee et al. 2009). Myc is a well-known proto-oncogene, and many associations between Myc and oncogenesis have been reported in PCa. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Few effective therapies exist for the treatment of castration-resistant prostate cancer (CRPC). Recent evidence suggests that CRPC may be caused by augmented androgen/androgen receptor (AR) signaling, generally involving AR overexpression. Aberrant androgen/AR signaling associated with AR overexpression also plays a key role in prostate carcinogenesis. Although AR overexpression could be attributed to gene amplification, only 10-20% of CRPCs exhibit AR gene amplification, and aberrant AR expression in the remaining instances of CRPC is thought to be attributed to transcriptional, translational, and post-translational mechanisms. Overexpression of AR at the protein level, as well as the mRNA level, has been found in CRPC, suggesting a key role for transcriptional regulation of AR expression. Since the analysis of the AR promoter region in the 1990s, several transcription factors have been reported to regulate AR transcription. In this review, we discuss the molecules involved in the control of AR gene expression, with emphasis on its transcriptional control by transcription factors in prostate cancer. We also consider the therapeutic potential of targeting AR expression.
    Preview · Article · Apr 2011 · Journal of Molecular Endocrinology
  • [Show abstract] [Hide abstract]
    ABSTRACT: The author describes the work which has been done on the steady-state mathematical model for the DC-AC inverters for the US Space Shuttle. The mathematical model is based on input/output data which describe the operation of the DC-AC inverters. Two methods of modeling were used, namely, the least-squares method and a method using a set of orthogonal polynomials. The reason for this mathematical model of the DC-AC inverters was to provide a computer program which could be used by the Electrical Power Distribution Lab. at the Johnson Space Center for simulation of steady-state operations. These data were modeled to produce a set of equations which approximate the output conditions and also some of the input conditions. These equations were then incorporated into a computer program written in Pascal
    No preview · Conference Paper · May 1989
Show more