Androgen receptor level controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line

Wang, Long G.; Ossowski, Liliana; Ferrari, Anna C.

doi:10.1038/sj.onc.1207654

Cited by 51 publications

(60 citation statements)

References 43 publications

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“…Therefore, inhibition of androgen receptor mRNA synthesis or stability contributes to the overall effect of LAQ824 on androgen receptor level. Consistent with this notion, the loss of an uncharacterized androgen receptor transcription suppressor was observed in a LNCaP-derived cell line that overexpresses androgen receptor (44). Expression of the androgen receptor suppressor complex could be partially induced by HDAC inhibitors (44).…”

Section: Discussionsupporting

confidence: 66%

Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824

Chen

Shao

Wang

et al. 2005

Molecular Cancer Therapeutics

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Androgen receptor plays a critical role in the development of primary as well as advanced hormone-refractory prostate cancer. Therefore, ablation of androgen receptor from prostate cancer cells is an interesting concept for developing a new therapy not only for androgendependent prostate cancer but also for metastatic hormone-refractory prostate cancer, for which there is no effective treatment available. We report here that LAQ824, a cinnamyl hydroxamatic acid histone deacetylase inhibitor currently in human clinical trials, effectively depleted androgen receptor in prostate cancer cells at nanomolar concentrations. LAQ824 seemed capable of depleting both the mutant and wild-type androgen receptors in either androgen-dependent and androgen-independent prostate cancer cells. Although LAQ824 may exert its effect through multiple mechanisms, several lines of evidence suggest that inactivation of the heat shock protein-90 (Hsp90) molecular chaperone is involved in LAQ824-induced androgen receptor depletion. Besides androgen receptor, LAQ824 reduced the level of Hsp90 client proteins HER-2 (ErbB2), Akt/ PKB, and Raf-1 in LNCaP cells. Another Hsp90 inhibitor, 17-allyamino-17-demethoxygeldanamycin (17-AAG), also induced androgen receptor diminution. LAQ824 induced Hsp90 acetylation in LNCaP cells, which resulted in inhibition of its ATP-binding activity, dissociation of Hsp90-androgen receptor complex, and proteasomemediated degradation of androgen receptor. Consequently, LAQ824 blocked androgen-induced prostate-specific antigen production in LNCaP cells. LAQ824 effectively inhibited cell proliferation and induced apoptosis of these prostate cancer cells. These results reveal that LAQ824 is a potent agent for depletion of androgen receptor and a potential new drug for prostate cancer. [Mol Cancer Ther 2005;4(9):1311 -9]

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Section: Discussionsupporting

confidence: 66%

Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824

Chen

Shao

Wang

et al. 2005

Molecular Cancer Therapeutics

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“…Significantly, it has been found that this suppressor protein(s) could be induced to re-express in AI cells through histone deacetylase inhibitors, such as trichostatin A, sodium butyrate or suberoylanilide hydroxamic acid (SAHA). Consequently, a normal AR function was restored as indicated by regaining an androgen-dependent phenotype and apoptotic sensitivity to chemotherapeutic agents (24)(25)(26)(27). Consistent with these findings, histone deacetylase inhibitors LAQ824 and SAHA have also been reported to repress AR at both the transcriptional and posttranslational levels (28,29).…”

Section: Downregulation Of Ar Expression By Peitc Through Epigenetic supporting

confidence: 69%

“…We recently demonstrated that several genes, including p21, Bax, PSA and the AR suppressor (ARS) were repressed in androgenindependent but not in androgen-dependent cells. The silencing of PSA and ARS has been shown to be the likely result of CpG island methylation (25,27). The silencing of p21, Bax and ARS may also be associated with both the drug resistance of cancer cells to chemotherapeutic agents and the androgen-independent progression of the disease (25,27,47).…”

Section: Restoration Of Gstp1 Expression By Peitc Via Cpg Island Demementioning

confidence: 99%

“…The silencing of PSA and ARS has been shown to be the likely result of CpG island methylation (25,27). The silencing of p21, Bax and ARS may also be associated with both the drug resistance of cancer cells to chemotherapeutic agents and the androgen-independent progression of the disease (25,27,47). Thus, restoration of the expression of silenced genes, via demethylation of the CpG island, may correct the aberrations associated with carcinogenesis and may prevent androgenindependent progression.…”

Section: Restoration Of Gstp1 Expression By Peitc Via Cpg Island Demementioning

confidence: 99%

“…PEITC has been recognized as an inducer of phase II detoxification enzymes, GSTs (48,49). To investigate the mechanism of PEITC to induce GSTP1, LNCaP AD and its sub-line LNCaP AI (24,25,27) were exposed to PEITC. The status of the methylated and the unmethylated forms of GSTP1 was measured by methylation-specific PCR (MSP) (50,51) and quantified by pyrosequencing.…”

Section: Restoration Of Gstp1 Expression By Peitc Via Cpg Island Demementioning

confidence: 99%

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Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (Review)

Wang¹

2010

Int J Oncol

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Abstract. Prostate cancer is one of the most commonly diagnosed cancers in men. The number of affected men is expected to rapidly increase as the population of males over the age of 50 grows worldwide. For patients who are not cured by local treatment and experience metastatic disease, neither androgen ablation nor chemotherapy can abrogate progression and death from androgen-independent/hormonerefractory disease. Therefore, finding strategies for the prevention of prostate cancer initiation and disease progression is a medical challenge. Consumption of cruciferous vegetables has been reported to be associated with reduced incidence of prostate cancer cases. The isothiocyanates, including phenethyl isothiocyanate (PEITC), from cruciferous vegetables have been demonstrated as active components responsible for chemoprevention. In this review, we summarize the recent findings of PEITC on prostate cancer prevention with an emphasis on epigenetic mechanisms. Studies have indicated that PEITC mediates gene regulation, such as downregulation of androgen receptor expression and induction of endogenous cyclin-dependent kinase inhibitors, p21 and p27. The gene for detoxifying enzyme π-class glutathione S-transferase (GSTP1), silenced in the vast majority of prostate tumor cells, could be reactivated and the enzymatic function recovered. This may be through epigenetic mechanisms as PEITC is a dual inhibitor of histone deacetylases and aberrant CpG island methylation of various genes. The epigenetic regulation may play a critical role, along with interactive mechanisms including the disruption of microtubule polymerization, in prostate cancer prevention by PEITC. These mechanisms target and correct the aberrations fundamental to the initiation and progression of carcinogenesis in cells, and restoring the cells to a more normal state. Inhibiting and eliminating cancer cells forms the basis of cancer prevention. Contents Introduction 2. Consumption of Brassica vegetables reduces prostatecancer risk 3. Downregulation of AR expression by PEITC through epigenetic mechanisms 4. Restoration of GSTP1 expression by PEITC via CpG island demethylation 5. PEITC inhibits prostate tumors and CGI methylation of the MGMT gene in TRAMP mice 6. Induction of endogenous cdk inhibitors by PEITC 7. Summary and conclusions IntroductionProstate cancer is the most commonly diagnosed cancer in men in the US. There were an expected 192,280 new cases and 27,360 deaths from prostate cancer in 2009 (1). Prostate cancer is usually found in elderly men. The prevalence of prostatic intraepithelial neoplasia and proliferative inflammatory atrophy, which are believed to be precursors of prostate cancers, may have a long latency period of ten or more years before developing into invasive carcinomas (2,3). Such factors lend credence to the growing belief that any delay in the time course of neoplastic development, achieved through pharmacological, hormonal and nutritional intervention, could result in a substantial reduction in the incidence of tumors. Even a ...

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Regulation of androgen receptor levels: Implications for prostate cancer progression and therapy

Burnstein

2005

J of Cellular Biochemistry

105

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Androgen deprivation has been the standard therapy for advanced and metastatic prostate cancer for over half a century, as prostate tumors are initially dependent on androgens for growth and survival. Unfortunately, in most patients undergoing androgen ablation, relapse (recurrent tumor growth) eventually occurs. The actions of the principal androgens, testosterone and dihydrotestosterone (DHT), are mediated via androgen receptors (ARs), ligand-activated transcription factors that belong to the nuclear receptor superfamily. Because of the presence of transcriptionally active ARs in tumors from recurrent or androgen-independent disease, there is a heightened interest in new therapeutic paradigms that target the AR and its regulatory pathways. The regulation of AR levels is highly complex with control exerted by several pathways and in a cell-, tissue-, and developmental-stage specific manner. Androgens are important regulators of AR mRNA and protein through transcriptional and post-transcriptional mechanisms. This article reviews the evidence implicating the AR in recurrent prostate cancer and discusses the multiple mechanisms that regulate AR levels in normal and neoplastic cells. The complexity of AR regulation suggests that there will be an ample array of potential new drug targets for modulating levels of this receptor, a key signaling molecule in prostate cancer.

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Androgen receptor level controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line

Cited by 51 publications

References 43 publications

Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824

Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824

Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (Review)

Regulation of androgen receptor levels: Implications for prostate cancer progression and therapy

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