Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen Treatment

Patients with advanced prostate carcinoma are often treated with an androgen deprivation therapy but long-term treatment can result in a metastatic castration-resistant prostate cancer. This is a more aggressive, untreatable tumor recurrence often containing areas of neuroendocrine differentiated pr...

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Main Authors: Marc Wiesehöfer, Elena Dilara Czyrnik, Martin Spahn, Saskia Ting, Henning Reis, Jaroslaw Thomas Dankert, Gunther Wennemuth
Format: Article
Language:English
Published: MDPI AG 2021-02-01
Series:Cancers
Subjects:
Online Access:https://www.mdpi.com/2072-6694/13/3/578
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spelling doaj-30afa0f11c7344aaa9483227a636068b2021-02-03T00:03:25ZengMDPI AGCancers2072-66942021-02-011357857810.3390/cancers13030578Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen TreatmentMarc Wiesehöfer0Elena Dilara Czyrnik1Martin Spahn2Saskia Ting3Henning Reis4Jaroslaw Thomas Dankert5Gunther Wennemuth6Department of Anatomy, University Duisburg-Essen, D-45147 Essen, GermanyDepartment of Anatomy, University Duisburg-Essen, D-45147 Essen, GermanyDepartment of Urology, Lindenhofspital Bern, CHE-3012 Bern, SwitzerlandInstitute of Pathology, University Duisburg-Essen, D-45147 Essen, GermanyInstitute of Pathology, University Duisburg-Essen, D-45147 Essen, GermanyDepartment of Anatomy, University Duisburg-Essen, D-45147 Essen, GermanyDepartment of Anatomy, University Duisburg-Essen, D-45147 Essen, GermanyPatients with advanced prostate carcinoma are often treated with an androgen deprivation therapy but long-term treatment can result in a metastatic castration-resistant prostate cancer. This is a more aggressive, untreatable tumor recurrence often containing areas of neuroendocrine differentiated prostate cancer cells. Using an in vitro model of NE-like cancer cells, it could previously be shown that neuroendocrine differentiation of LNCaP cells leads to a strong deregulation of mRNA and miRNA expression. We observe elevated RNA and protein levels of AKT Serine/Threonine Kinase 3 (AKT3) in neuroendocrine-like LNCaP cells. We used prostate resections from patients with neuroendocrine prostate cancer to validate these results and detect a co-localization of neuroendocrine marker genes with AKT3. Analysis of downstream target genes FOXO3A and GSK3 strengthens the assumption AKT3 may play a role in neuroendocrine differentiation. Overexpression of AKT3 shows an increased survival rate of LNCaP cells after apoptosis induction, which in turn reflects the significance in vivo or for treatment. Furthermore, miR-17, −20b and −106b, which are decreased in neuroendocrine-like LNCaP cells, negatively regulate AKT3 biosynthesis. Our findings demonstrate AKT3 as a potential therapeutic target and diagnostic tool in advanced neuroendocrine prostate cancer and a new mRNA–miRNA interaction with a potential role in neuroendocrine differentiation of prostate cancer.https://www.mdpi.com/2072-6694/13/3/578prostate cancerneuroendocrine differentiationNE-like LNCaP cellsAKT3miR-17 family
collection DOAJ
language English
format Article
sources DOAJ
author Marc Wiesehöfer
Elena Dilara Czyrnik
Martin Spahn
Saskia Ting
Henning Reis
Jaroslaw Thomas Dankert
Gunther Wennemuth
spellingShingle Marc Wiesehöfer
Elena Dilara Czyrnik
Martin Spahn
Saskia Ting
Henning Reis
Jaroslaw Thomas Dankert
Gunther Wennemuth
Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen Treatment
Cancers
prostate cancer
neuroendocrine differentiation
NE-like LNCaP cells
AKT3
miR-17 family
author_facet Marc Wiesehöfer
Elena Dilara Czyrnik
Martin Spahn
Saskia Ting
Henning Reis
Jaroslaw Thomas Dankert
Gunther Wennemuth
author_sort Marc Wiesehöfer
title Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen Treatment
title_short Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen Treatment
title_full Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen Treatment
title_fullStr Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen Treatment
title_full_unstemmed Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen Treatment
title_sort increased expression of akt3 in neuroendocrine differentiated prostate cancer cells alters the response towards anti-androgen treatment
publisher MDPI AG
series Cancers
issn 2072-6694
publishDate 2021-02-01
description Patients with advanced prostate carcinoma are often treated with an androgen deprivation therapy but long-term treatment can result in a metastatic castration-resistant prostate cancer. This is a more aggressive, untreatable tumor recurrence often containing areas of neuroendocrine differentiated prostate cancer cells. Using an in vitro model of NE-like cancer cells, it could previously be shown that neuroendocrine differentiation of LNCaP cells leads to a strong deregulation of mRNA and miRNA expression. We observe elevated RNA and protein levels of AKT Serine/Threonine Kinase 3 (AKT3) in neuroendocrine-like LNCaP cells. We used prostate resections from patients with neuroendocrine prostate cancer to validate these results and detect a co-localization of neuroendocrine marker genes with AKT3. Analysis of downstream target genes FOXO3A and GSK3 strengthens the assumption AKT3 may play a role in neuroendocrine differentiation. Overexpression of AKT3 shows an increased survival rate of LNCaP cells after apoptosis induction, which in turn reflects the significance in vivo or for treatment. Furthermore, miR-17, −20b and −106b, which are decreased in neuroendocrine-like LNCaP cells, negatively regulate AKT3 biosynthesis. Our findings demonstrate AKT3 as a potential therapeutic target and diagnostic tool in advanced neuroendocrine prostate cancer and a new mRNA–miRNA interaction with a potential role in neuroendocrine differentiation of prostate cancer.
topic prostate cancer
neuroendocrine differentiation
NE-like LNCaP cells
AKT3
miR-17 family
url https://www.mdpi.com/2072-6694/13/3/578
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