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Mithramycin Targets Sp1 and The Androgen Receptor Transcription Level—Potential Therapeutic Role in Advanced Prostate Cancer

Multiple lines of evidence implicate over-expression and activation of the androgen receptor (AR) in the progression of prostate cancer (PC) to androgen-independence (AI) and resistance to therapy. The mechanisms leading to AR over-expression are not fully understood but binding of Sp1 to specific S...

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Autores principales: Wang, Long G., Ferrari, Anna C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Libertas Academica 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3642134/
https://www.ncbi.nlm.nih.gov/pubmed/23662037
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author Wang, Long G.
Ferrari, Anna C.
author_facet Wang, Long G.
Ferrari, Anna C.
author_sort Wang, Long G.
collection PubMed
description Multiple lines of evidence implicate over-expression and activation of the androgen receptor (AR) in the progression of prostate cancer (PC) to androgen-independence (AI) and resistance to therapy. The mechanisms leading to AR over-expression are not fully understood but binding of Sp1 to specific Sp1-binding sites in the AR promoter and 5′-untranslated region (5′-UTR) was shown to up-regulate AR transcription. In this work, we further characterized the role of Sp1 in the control of AR transcription and explored its potential as a therapeutic target in androgen-dependent (AD) and independent (AI) LNCaP cells. We identified a pair of new Sp1-binding site in the 5′-UTR of AR which we named ARSp1-3. ARSp1-3 binds Sp1 with higher affinity than other known Sp1-binding sites in the promoter/5′-UTR and in transfection experiments, the ARSp1-3 reporter showed higher transcriptional activity in AI than in AD cells. Treatment of these cells with nanomolar concentrations of Mithramycin inhibited binding of Sp1 to its binding sites in the promoter/5′-UTR of the AR gene but more specifically the binding of ARSp1-3 while other regulatory elements of the AR promoter were not affected. Inhibition of Sp1 binding by Mithramycin decreased the AR transcription and transactivation of PSA reporter constructs. At the lowest concentrations, Mithramycin decreased endogenous AR protein and proliferation of AD and AI LNCaP cells. The combinations of Mithramycin with either paclitaxel or bicalutamide were highly synergistic. CONCLUSION: Sp1 binding induces AR transcription in LNCaP cells. The higher affinity of ARSp1-3 for Sp1 may support higher AR mRNA levels in AI than AD LNCaP cells. Mithramycin is a potent and specific inhibitor of Sp1 and AR transcription with potential, at very low concentrations, to enhance the efficacy of hormones or taxane based therapy in patients with recurrent or androgen-independent progression that sustain AR expression.
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spelling pubmed-36421342013-05-09 Mithramycin Targets Sp1 and The Androgen Receptor Transcription Level—Potential Therapeutic Role in Advanced Prostate Cancer Wang, Long G. Ferrari, Anna C. Transl Oncogenomics Original Research Multiple lines of evidence implicate over-expression and activation of the androgen receptor (AR) in the progression of prostate cancer (PC) to androgen-independence (AI) and resistance to therapy. The mechanisms leading to AR over-expression are not fully understood but binding of Sp1 to specific Sp1-binding sites in the AR promoter and 5′-untranslated region (5′-UTR) was shown to up-regulate AR transcription. In this work, we further characterized the role of Sp1 in the control of AR transcription and explored its potential as a therapeutic target in androgen-dependent (AD) and independent (AI) LNCaP cells. We identified a pair of new Sp1-binding site in the 5′-UTR of AR which we named ARSp1-3. ARSp1-3 binds Sp1 with higher affinity than other known Sp1-binding sites in the promoter/5′-UTR and in transfection experiments, the ARSp1-3 reporter showed higher transcriptional activity in AI than in AD cells. Treatment of these cells with nanomolar concentrations of Mithramycin inhibited binding of Sp1 to its binding sites in the promoter/5′-UTR of the AR gene but more specifically the binding of ARSp1-3 while other regulatory elements of the AR promoter were not affected. Inhibition of Sp1 binding by Mithramycin decreased the AR transcription and transactivation of PSA reporter constructs. At the lowest concentrations, Mithramycin decreased endogenous AR protein and proliferation of AD and AI LNCaP cells. The combinations of Mithramycin with either paclitaxel or bicalutamide were highly synergistic. CONCLUSION: Sp1 binding induces AR transcription in LNCaP cells. The higher affinity of ARSp1-3 for Sp1 may support higher AR mRNA levels in AI than AD LNCaP cells. Mithramycin is a potent and specific inhibitor of Sp1 and AR transcription with potential, at very low concentrations, to enhance the efficacy of hormones or taxane based therapy in patients with recurrent or androgen-independent progression that sustain AR expression. Libertas Academica 2006-10-11 /pmc/articles/PMC3642134/ /pubmed/23662037 Text en © 2006 the author(s), publisher and licensee Libertas Academica Ltd. This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.
spellingShingle Original Research
Wang, Long G.
Ferrari, Anna C.
Mithramycin Targets Sp1 and The Androgen Receptor Transcription Level—Potential Therapeutic Role in Advanced Prostate Cancer
title Mithramycin Targets Sp1 and The Androgen Receptor Transcription Level—Potential Therapeutic Role in Advanced Prostate Cancer
title_full Mithramycin Targets Sp1 and The Androgen Receptor Transcription Level—Potential Therapeutic Role in Advanced Prostate Cancer
title_fullStr Mithramycin Targets Sp1 and The Androgen Receptor Transcription Level—Potential Therapeutic Role in Advanced Prostate Cancer
title_full_unstemmed Mithramycin Targets Sp1 and The Androgen Receptor Transcription Level—Potential Therapeutic Role in Advanced Prostate Cancer
title_short Mithramycin Targets Sp1 and The Androgen Receptor Transcription Level—Potential Therapeutic Role in Advanced Prostate Cancer
title_sort mithramycin targets sp1 and the androgen receptor transcription level—potential therapeutic role in advanced prostate cancer
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3642134/
https://www.ncbi.nlm.nih.gov/pubmed/23662037
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