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TPL2/COT/MAP3K8 (TPL2) Activation Promotes Androgen Depletion-Independent (ADI) Prostate Cancer Growth

BACKGROUND: Despite its initial positive response to hormone ablation therapy, prostate cancers invariably recur in more aggressive, treatment resistant forms. The lack of our understanding of underlying genetic alterations for the transition from androgen-dependent (AD) to ADI prostate cancer growt...

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Autores principales: Jeong, Joseph H., Bhatia, Ayesha, Toth, Zsolt, Oh, Soohwan, Inn, Kyung-Soo, Liao, Chun-Peng, Roy-Burman, Pradip, Melamed, Jonathan, Coetzee, Gerhard A., Jung, Jae U.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022761/
https://www.ncbi.nlm.nih.gov/pubmed/21267413
http://dx.doi.org/10.1371/journal.pone.0016205
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author Jeong, Joseph H.
Bhatia, Ayesha
Toth, Zsolt
Oh, Soohwan
Inn, Kyung-Soo
Liao, Chun-Peng
Roy-Burman, Pradip
Melamed, Jonathan
Coetzee, Gerhard A.
Jung, Jae U.
author_facet Jeong, Joseph H.
Bhatia, Ayesha
Toth, Zsolt
Oh, Soohwan
Inn, Kyung-Soo
Liao, Chun-Peng
Roy-Burman, Pradip
Melamed, Jonathan
Coetzee, Gerhard A.
Jung, Jae U.
author_sort Jeong, Joseph H.
collection PubMed
description BACKGROUND: Despite its initial positive response to hormone ablation therapy, prostate cancers invariably recur in more aggressive, treatment resistant forms. The lack of our understanding of underlying genetic alterations for the transition from androgen-dependent (AD) to ADI prostate cancer growth hampers our ability to develop target-driven therapeutic strategies for the efficient treatment of ADI prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: By screening a library of activated human kinases, we have identified TPL2, encoding a serine/threonine kinase, as driving ADI prostate cancer growth. TPL2 activation by over-expressing either wild-type or a constitutively activated form of TPL2 induced ADI growth, whereas the suppression of TPL2 expression and its kinase activity in ADI prostate cancer cells inhibited cell proliferation under androgen-depleted conditions. Most importantly, TPL2 is upregulated in ADI prostate cancers of both the Pten deletion mouse model and the clinical prostate cancer specimens. CONCLUSIONS/SIGNIFICANCE: Together these data suggest that TPL2 kinase plays a critical role in the promotion of ADI prostate cancer progression. Furthermore, the suppression of TPL2 diminishes ADI prostate cancer growth and a high frequency of TPL2 overexpression in human ADI prostate cancer samples validates TPL2 as a target for the treatment of this deadly disease.
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spelling pubmed-30227612011-01-25 TPL2/COT/MAP3K8 (TPL2) Activation Promotes Androgen Depletion-Independent (ADI) Prostate Cancer Growth Jeong, Joseph H. Bhatia, Ayesha Toth, Zsolt Oh, Soohwan Inn, Kyung-Soo Liao, Chun-Peng Roy-Burman, Pradip Melamed, Jonathan Coetzee, Gerhard A. Jung, Jae U. PLoS One Research Article BACKGROUND: Despite its initial positive response to hormone ablation therapy, prostate cancers invariably recur in more aggressive, treatment resistant forms. The lack of our understanding of underlying genetic alterations for the transition from androgen-dependent (AD) to ADI prostate cancer growth hampers our ability to develop target-driven therapeutic strategies for the efficient treatment of ADI prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: By screening a library of activated human kinases, we have identified TPL2, encoding a serine/threonine kinase, as driving ADI prostate cancer growth. TPL2 activation by over-expressing either wild-type or a constitutively activated form of TPL2 induced ADI growth, whereas the suppression of TPL2 expression and its kinase activity in ADI prostate cancer cells inhibited cell proliferation under androgen-depleted conditions. Most importantly, TPL2 is upregulated in ADI prostate cancers of both the Pten deletion mouse model and the clinical prostate cancer specimens. CONCLUSIONS/SIGNIFICANCE: Together these data suggest that TPL2 kinase plays a critical role in the promotion of ADI prostate cancer progression. Furthermore, the suppression of TPL2 diminishes ADI prostate cancer growth and a high frequency of TPL2 overexpression in human ADI prostate cancer samples validates TPL2 as a target for the treatment of this deadly disease. Public Library of Science 2011-01-18 /pmc/articles/PMC3022761/ /pubmed/21267413 http://dx.doi.org/10.1371/journal.pone.0016205 Text en Jeong et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Jeong, Joseph H.
Bhatia, Ayesha
Toth, Zsolt
Oh, Soohwan
Inn, Kyung-Soo
Liao, Chun-Peng
Roy-Burman, Pradip
Melamed, Jonathan
Coetzee, Gerhard A.
Jung, Jae U.
TPL2/COT/MAP3K8 (TPL2) Activation Promotes Androgen Depletion-Independent (ADI) Prostate Cancer Growth
title TPL2/COT/MAP3K8 (TPL2) Activation Promotes Androgen Depletion-Independent (ADI) Prostate Cancer Growth
title_full TPL2/COT/MAP3K8 (TPL2) Activation Promotes Androgen Depletion-Independent (ADI) Prostate Cancer Growth
title_fullStr TPL2/COT/MAP3K8 (TPL2) Activation Promotes Androgen Depletion-Independent (ADI) Prostate Cancer Growth
title_full_unstemmed TPL2/COT/MAP3K8 (TPL2) Activation Promotes Androgen Depletion-Independent (ADI) Prostate Cancer Growth
title_short TPL2/COT/MAP3K8 (TPL2) Activation Promotes Androgen Depletion-Independent (ADI) Prostate Cancer Growth
title_sort tpl2/cot/map3k8 (tpl2) activation promotes androgen depletion-independent (adi) prostate cancer growth
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022761/
https://www.ncbi.nlm.nih.gov/pubmed/21267413
http://dx.doi.org/10.1371/journal.pone.0016205
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