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Molecular Pharmacology

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Research ArticleArticle

ADP Ribosylation Factor 6 Promotes Contraction and Proliferation, Suppresses Apoptosis and Is Specifically Inhibited by NAV2729 in Prostate Stromal Cells

Ruixiao Wang, Stephanie Schneider, Oliver T. Keppler, Bingsheng Li, Beata Rutz, Anna Ciotkowska, Christian G. Stief and Martin Hennenberg
Molecular Pharmacology October 2021, 100 (4) 356-371; DOI: https://doi.org/10.1124/molpharm.121.000304
Ruixiao Wang
Department of Urology, University Hospital Munich, LMU Munich, Munich, Germany (R.W., B.L., B.R., A.C., C.G.S., M.H.); and Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU Munich, Munich, Germany (S.S., O.T.K.)
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Stephanie Schneider
Department of Urology, University Hospital Munich, LMU Munich, Munich, Germany (R.W., B.L., B.R., A.C., C.G.S., M.H.); and Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU Munich, Munich, Germany (S.S., O.T.K.)
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Oliver T. Keppler
Department of Urology, University Hospital Munich, LMU Munich, Munich, Germany (R.W., B.L., B.R., A.C., C.G.S., M.H.); and Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU Munich, Munich, Germany (S.S., O.T.K.)
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Bingsheng Li
Department of Urology, University Hospital Munich, LMU Munich, Munich, Germany (R.W., B.L., B.R., A.C., C.G.S., M.H.); and Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU Munich, Munich, Germany (S.S., O.T.K.)
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Beata Rutz
Department of Urology, University Hospital Munich, LMU Munich, Munich, Germany (R.W., B.L., B.R., A.C., C.G.S., M.H.); and Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU Munich, Munich, Germany (S.S., O.T.K.)
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Anna Ciotkowska
Department of Urology, University Hospital Munich, LMU Munich, Munich, Germany (R.W., B.L., B.R., A.C., C.G.S., M.H.); and Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU Munich, Munich, Germany (S.S., O.T.K.)
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Christian G. Stief
Department of Urology, University Hospital Munich, LMU Munich, Munich, Germany (R.W., B.L., B.R., A.C., C.G.S., M.H.); and Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU Munich, Munich, Germany (S.S., O.T.K.)
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Martin Hennenberg
Department of Urology, University Hospital Munich, LMU Munich, Munich, Germany (R.W., B.L., B.R., A.C., C.G.S., M.H.); and Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU Munich, Munich, Germany (S.S., O.T.K.)
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Abstract

The presumed ADP ribosylation factor (ARF) 6 inhibitor NAV2729 inhibits human prostate smooth muscle contraction and proliferation of stromal cells, which are driving factors of voiding symptoms in benign prostatic hyperplasia (BPH). However, its specificity and a confirmed role of ARF6 for smooth muscle contraction are still pending. Here, we generated monoclonal ARF6 knockouts in human prostate stromal cells (WPMY-1), and characterized phenotypes of contractility, growth-related functions, and susceptibility to NAV2729 in knockout and control clones. ARF6 knockout was verified by Western blot. Knockout clones showed impaired contraction and actin organization, reduced proliferation and viability, and increased apoptosis and cell death. In ARF6-expressing control clones, NAV2729 (5 µM) strongly inhibited contraction (67% inhibition across all three control clones), actin organization (72%), proliferation (97%), and viability (up to 82%), and increased apoptosis (5-fold) and cell death (6-fold). In ARF6 knockouts, effects of NAV2729 (5 µM) were widely reduced, including lacking or minor effects on contractions (0% inhibition across all three knockout clones), actin (18%) and proliferation (13%), and lacking increases of apoptosis and cell death. Viability was reduced by NAV2729 with an IC50 of 3.3 µM across all three ARF6 control clones, but of 4.5–8.2 µM in ARF6 knockouts. In conclusion, ARF6 promotes prostate smooth muscle contraction and proliferation of stromal cells. Both are inhibited by NAV2729, which showed high specificity for ARF6 up to 5 µM and represents an attractive compound in the context of BPH. Considering the relevance of smooth muscle-based diseases, shared roles of ARF6 in other smooth muscle types merit further investigation.

SIGNIFICANCE STATEMENT By knockout of ARF6 in prostate stromal cells, this study demonstrates the involvement of ARF6 in promotion of prostate smooth muscle contraction and stromal growth, and defines concentration ranges for their ARF6-specific inhibition by NAV2729. Besides the context of benign prostatic hyperplasia and lower urinary tract symptoms, analog ARF6 functions in contraction and growth appear possible in other smooth muscle-rich organs, which merits further attention considering the high clinical relevance of smooth muscle-based diseases.

Footnotes

    • Received April 4, 2021.
    • Accepted July 30, 2021.
  • This work was supported by the Deutsche Forschungsgemeinschaft [Grant HE 5825/8-1]; and the Chinese Scholarship Council (CSC) [Grant 201608210185] (R.W.) and [Grant 201706370083] (B.L.).

  • https://doi.org/10.1124/molpharm.121.000304.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 100 (4)
Molecular Pharmacology
Vol. 100, Issue 4
1 Oct 2021
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Research ArticleArticle

ARF6 Promotes Contraction, Growth of Prostate Stromal Cells

Ruixiao Wang, Stephanie Schneider, Oliver T. Keppler, Bingsheng Li, Beata Rutz, Anna Ciotkowska, Christian G. Stief and Martin Hennenberg
Molecular Pharmacology October 1, 2021, 100 (4) 356-371; DOI: https://doi.org/10.1124/molpharm.121.000304

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Research ArticleArticle

ARF6 Promotes Contraction, Growth of Prostate Stromal Cells

Ruixiao Wang, Stephanie Schneider, Oliver T. Keppler, Bingsheng Li, Beata Rutz, Anna Ciotkowska, Christian G. Stief and Martin Hennenberg
Molecular Pharmacology October 1, 2021, 100 (4) 356-371; DOI: https://doi.org/10.1124/molpharm.121.000304
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