Transgelin functions as a suppressor via inhibition of ARA54-enhanced androgen receptor transactivation and prostate cancer cell growth.

George Whipple Laboratory for Cancer Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, New York 14642, USA.
Molecular Endocrinology (Impact Factor: 4.2). 03/2007; 21(2):343-58. DOI: 10.1210/me.2006-0104
Source: PubMed

ABSTRACT The androgen receptor (AR) requires coregulators for its optimal function. However, whether AR coregulators further need interacting protein(s) for their proper function remains unclear. Here we describe transgelin as the first ARA54-associated negative modulator for AR. Transgelin suppressed ARA54-enhanced AR function in ARA54-positive, but not in ARA54-negative, cells. Transgelin suppressed AR transactivation via interruption of ARA54 homodimerization and AR-ARA54 heterodimerization, resulting in the cytoplasmic retention of AR and ARA54. Stable transfection of transgelin in LNCaP cells suppressed AR-mediated cell growth and prostate-specific antigen expression, whereas this suppressive effect was abolished by the addition of ARA54-small interfering RNA. Results from tissue surveys showing decreased expression of transgelin in prostate cancer specimens further strengthened the suppressor role of transgelin. Our findings reveal the novel mechanisms of how transgelin functions as a suppressor to inhibit prostate cancer cell growth. They also demonstrate that AR coregulators, like ARA54, might have dual in vivo roles functioning as both a direct coactivator and as an indirect mediator in AR function. The finding that a protein can modulate AR function without direct interaction with AR might provide a new therapeutic approach, with fewer side effects, to battle prostate cancer by targeting AR indirectly.

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Available from: Yu-Jia Chang, May 12, 2014
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    • "Paradoxically, there is previous evidence that transgelin is both a tumor suppressor and a variable tumor biomarker, depending on the tumor type, stage, and experimental model [4] [5] [6] [7] [8] [9] [10] [11] [12]. "
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    • "Several AR coregulators are upregulated in advanced prostate cancer (Culig and Bartsch 2006; Fujimoto et al. 2007; Heemers and Tindall 2007; Hu et al. 2004; Kahl et al. 2006; Nishimura et al. 2003; Yang et al. 2007a, b) and increase androgen sensitivity and ligand promiscuity of wild-type AR and some AR mutants (Yeh et al. 1997, 1998; Heinlein and Chang 2002; Rahman et al. 2004). AR-interacting proteins could alter the AR functions both in the prostate cancer cells and in cancerassociated stromal cells. "
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    ABSTRACT: The androgen depletion therapy (ADT) has become the major treatment for the cancer patients through the use of chemical castration and/or antiandrogens, yet the therapy eventually fails and cancers progress to more advanced stages. The mutation, amplification, overexpression of AR, and cross-talk between AR, AR co-regulators, and other growth factor pathways have provided potential explanations for the failure of androgen ablation therapies in some cases. However, whether the differential AR roles in different types of prostate cells could contribute to the failure of ADT remains unclear and will be the focus of this review. AR expresses in both stromal and epithelial compartments of prostate. It has been shown that there are three basic types of prostatic epithelial cells: (i) cytokeratin 8 (CK8)-positive, CK5-negative luminal cells, (ii) CK5/CK8-double positive intermediate cells, and (iii) CK8-negative, CK5-positive basal cells. In addition to prostatic stromal cells, AR expression could be detected in some basal cells, some intermediate cells, and all luminal cells in prostate. By Cre-LoxP strategy, the prostate epithelium-specific AR knockout (pes-ARKO) and inducible-cre ARKO mice were recently established and have allowed the field to address the differential and distinct AR roles in different types of prostatic cells. These ARKO mice were bred with TRAMP prostate cancer model, and results from these models suggest that (i) prostatic epithelial AR plays dual roles as a suppressor of basal cell proliferation and as a survival factor for luminal cells, and (ii) the stromal AR plays a proliferator role to support the epithelial cell survival and proliferation. Using microarray analysis of primary tumor cells isolated from the prostate tumors of pes-ARKO-TRAMP mice, it was found that a series of metastatic genes were altered and responsible for the higher invasiveness and metastatic rates. These recent ARKO animal studies not only advance our understanding of the differential roles of AR in different type of prostatic cells, but also closely reflect the pathological changes for the patients undergoing the ADT. Together, these findings provide new evidences to support the potential beneficial effects of intermittent ADT therapy, and they also urge the development of cell type and stage selective anti-AR therapies for the prostate cancer patients.
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