The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer.

Alternative Splicing Animals Benzamides Cell Line, Tumor Cell Proliferation / drug effects Clorgyline / pharmacology Drug Resistance, Neoplasm / drug effects Enzyme Stability Gene Expression Regulation, Enzymologic / drug effects Gene Expression Regulation, Neoplastic / drug effects Humans Male Mice Mice, Nude Mice, SCID Monoamine Oxidase / chemistry Monoamine Oxidase Inhibitors / pharmacology Neoplastic Cells, Circulating / metabolism Nitriles Phenelzine / pharmacology Phenylthiohydantoin / analogs & derivatives Prostatic Neoplasms, Castration-Resistant / drug therapy Receptors, Androgen / genetics Signal Transduction / drug effects Up-Regulation / drug effects Xenograft Model Antitumor Assays

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
01 06 2020
Historique:
received: 30 11 2017
accepted: 06 03 2020
entrez: 3 6 2020
pubmed: 3 6 2020
medline: 25 8 2020
Statut: epublish

Résumé

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the androgen receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC.

Identifiants

DOI: 10.1038/s41467-020-15396-5 PMID: 32483206 PMC: PMC7264333
pubmed: 32483206
doi: 10.1038/s41467-020-15396-5
pii: 10.1038/s41467-020-15396-5
pmc: PMC7264333
doi:

Substances chimiques

AR protein, human 0
Benzamides 0
Monoamine Oxidase Inhibitors 0
Nitriles 0
Receptors, Androgen 0
Phenylthiohydantoin 2010-15-3
enzalutamide 93T0T9GKNU
Monoamine Oxidase EC 1.4.3.4
monoamine oxidase A, human EC 1.4.3.4.
Clorgyline LYJ16FZU9Q
Phenelzine O408N561GF

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2689

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Auteurs

Keliang Wang (K)

Department of Urology, The 4th Affiliated Hospital of Harbin Medical University, NHC Key Lab of Molecular Probes and Targeted Diagnosis and Therapy, Harbin, 150001, China.
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.

Jie Luo (J)

George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.

Shuyuan Yeh (S)

George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.
ORCID: 0000-0002-5329-2321

Bosen You (B)

Department of Urology, The 4th Affiliated Hospital of Harbin Medical University, NHC Key Lab of Molecular Probes and Targeted Diagnosis and Therapy, Harbin, 150001, China.
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.

Jialin Meng (J)

George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.
ORCID: 0000-0002-4622-833X

Philip Chang (P)

Department of Neurology, Kaiser Permanente Santa Clara Medical Center, Santa Clara, CA, 95051, USA.

Yuanjie Niu (Y)

Tianjin Institute of Urology, Tianjin Medical University, Tianjin, 300211, China.

Gonghui Li (G)

Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.

Changxue Lu (C)

Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center, and James Buchanan Brady Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Yezi Zhu (Y)

Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center, and James Buchanan Brady Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Emmanuel S Antonarakis (ES)

Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center, and James Buchanan Brady Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Jun Luo (J)

Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center, and James Buchanan Brady Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Chi-Ping Huang (CP)

Sex Hormone Research Center, Department of Urology, China Medical University and Hospital, Taichung, 404, Taiwan.

Wanhai Xu (W)

Department of Urology, The 4th Affiliated Hospital of Harbin Medical University, NHC Key Lab of Molecular Probes and Targeted Diagnosis and Therapy, Harbin, 150001, China. xuwanhai@163.com.

Chawnshang Chang (C)

George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA. chang@urmc.rochester.edu.
Sex Hormone Research Center, Department of Urology, China Medical University and Hospital, Taichung, 404, Taiwan. chang@urmc.rochester.edu.

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Épissage des ARN › Épissage alternatif › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Eucaryotes › Animaux › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Benzoates › Benzamides › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Composés chimiques organiques › Amines › Propylamines › Clorgiline › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Stabilité protéique › Stabilité enzymatique › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes codant pour des enzymes › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souches mutantes de souris › Souris nude › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souches mutantes de souris › Souris SCID › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Oxidoreductases acting on CH-NH2 group donors › Monoamine oxidase › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de la monoamine oxydase › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Métastase tumorale › Cellules tumorales circulantes › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Composés chimiques organiques › Nitriles › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Composés chimiques organiques › Hydrazines › Phénelzine › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Imidazoles › Imidazolidines › Hydantoïnes › Thiohydantoïnes › 3-Phényl-2-thiohydantoïne › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Tumeurs prostatiques résistantes à la castration › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteurs aux androgènes › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation positive › The MAO inhibitors phenelzine and clorgyline...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › The MAO inhibitors phenelzine and clorgyline...