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PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy

PTEN loss is prognostic for patient relapse post-radiotherapy in prostate cancer (CaP). Infiltration of tumor-associated macrophages (TAMs) is associated with reduced disease-free survival following radical prostatectomy. However, the association between PTEN loss, TAM infiltration and radiotherapy...

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Autores principales: Armstrong, Chris W.D., Maxwell, Pamela J., Ong, Chee Wee, Redmond, Kelly M., McCann, Christopher, Neisen, Jessica, Ward, George A., Chessari, Gianni, Johnson, Christopher, Crawford, Nyree T., LaBonte, Melissa J., Prise, Kevin M., Robson, Tracy, Salto-Tellez, Manuel, Longley, Daniel B., Waugh, David J.J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884961/
https://www.ncbi.nlm.nih.gov/pubmed/26799286
http://dx.doi.org/10.18632/oncotarget.6955
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author Armstrong, Chris W.D.
Maxwell, Pamela J.
Ong, Chee Wee
Redmond, Kelly M.
McCann, Christopher
Neisen, Jessica
Ward, George A.
Chessari, Gianni
Johnson, Christopher
Crawford, Nyree T.
LaBonte, Melissa J.
Prise, Kevin M.
Robson, Tracy
Salto-Tellez, Manuel
Longley, Daniel B.
Waugh, David J.J.
author_facet Armstrong, Chris W.D.
Maxwell, Pamela J.
Ong, Chee Wee
Redmond, Kelly M.
McCann, Christopher
Neisen, Jessica
Ward, George A.
Chessari, Gianni
Johnson, Christopher
Crawford, Nyree T.
LaBonte, Melissa J.
Prise, Kevin M.
Robson, Tracy
Salto-Tellez, Manuel
Longley, Daniel B.
Waugh, David J.J.
author_sort Armstrong, Chris W.D.
collection PubMed
description PTEN loss is prognostic for patient relapse post-radiotherapy in prostate cancer (CaP). Infiltration of tumor-associated macrophages (TAMs) is associated with reduced disease-free survival following radical prostatectomy. However, the association between PTEN loss, TAM infiltration and radiotherapy response of CaP cells remains to be evaluated. Immunohistochemical and molecular analysis of surgically-resected Gleason 7 tumors confirmed that PTEN loss correlated with increased CXCL8 expression and macrophage infiltration. However PTEN status had no discernable correlation with expression of other inflammatory markers by CaP cells, including TNF-α. In vitro, exposure to conditioned media harvested from irradiated PTEN null CaP cells induced chemotaxis of macrophage-like THP-1 cells, a response partially attenuated by CXCL8 inhibition. Co-culture with THP-1 cells resulted in a modest reduction in the radio-sensitivity of DU145 cells. Cytokine profiling revealed constitutive secretion of TNF-α from CaP cells irrespective of PTEN status and IR-induced TNF-α secretion from THP-1 cells. THP-1-derived TNF-α increased NFκB pro-survival activity and elevated expression of anti-apoptotic proteins including cellular inhibitor of apoptosis protein-1 (cIAP-1) in CaP cells, which could be attenuated by pre-treatment with a TNF-α neutralizing antibody. Treatment with a novel IAP antagonist, AT-IAP, decreased basal and TNF-α-induced cIAP-1 expression in CaP cells, switched TNF-α signaling from pro-survival to pro-apoptotic and increased radiation sensitivity of CaP cells in co-culture with THP-1 cells. We conclude that targeting cIAP-1 can overcome apoptosis resistance of CaP cells and is an ideal approach to exploit high TNF-α signals within the TAM-rich microenvironment of PTEN-deficient CaP cells to enhance response to radiotherapy.
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spelling pubmed-48849612016-06-17 PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy Armstrong, Chris W.D. Maxwell, Pamela J. Ong, Chee Wee Redmond, Kelly M. McCann, Christopher Neisen, Jessica Ward, George A. Chessari, Gianni Johnson, Christopher Crawford, Nyree T. LaBonte, Melissa J. Prise, Kevin M. Robson, Tracy Salto-Tellez, Manuel Longley, Daniel B. Waugh, David J.J. Oncotarget Research Paper PTEN loss is prognostic for patient relapse post-radiotherapy in prostate cancer (CaP). Infiltration of tumor-associated macrophages (TAMs) is associated with reduced disease-free survival following radical prostatectomy. However, the association between PTEN loss, TAM infiltration and radiotherapy response of CaP cells remains to be evaluated. Immunohistochemical and molecular analysis of surgically-resected Gleason 7 tumors confirmed that PTEN loss correlated with increased CXCL8 expression and macrophage infiltration. However PTEN status had no discernable correlation with expression of other inflammatory markers by CaP cells, including TNF-α. In vitro, exposure to conditioned media harvested from irradiated PTEN null CaP cells induced chemotaxis of macrophage-like THP-1 cells, a response partially attenuated by CXCL8 inhibition. Co-culture with THP-1 cells resulted in a modest reduction in the radio-sensitivity of DU145 cells. Cytokine profiling revealed constitutive secretion of TNF-α from CaP cells irrespective of PTEN status and IR-induced TNF-α secretion from THP-1 cells. THP-1-derived TNF-α increased NFκB pro-survival activity and elevated expression of anti-apoptotic proteins including cellular inhibitor of apoptosis protein-1 (cIAP-1) in CaP cells, which could be attenuated by pre-treatment with a TNF-α neutralizing antibody. Treatment with a novel IAP antagonist, AT-IAP, decreased basal and TNF-α-induced cIAP-1 expression in CaP cells, switched TNF-α signaling from pro-survival to pro-apoptotic and increased radiation sensitivity of CaP cells in co-culture with THP-1 cells. We conclude that targeting cIAP-1 can overcome apoptosis resistance of CaP cells and is an ideal approach to exploit high TNF-α signals within the TAM-rich microenvironment of PTEN-deficient CaP cells to enhance response to radiotherapy. Impact Journals LLC 2016-01-20 /pmc/articles/PMC4884961/ /pubmed/26799286 http://dx.doi.org/10.18632/oncotarget.6955 Text en Copyright: © 2016 Armstrong et al. http://creativecommons.org/licenses/by/2.5/ 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 credited.
spellingShingle Research Paper
Armstrong, Chris W.D.
Maxwell, Pamela J.
Ong, Chee Wee
Redmond, Kelly M.
McCann, Christopher
Neisen, Jessica
Ward, George A.
Chessari, Gianni
Johnson, Christopher
Crawford, Nyree T.
LaBonte, Melissa J.
Prise, Kevin M.
Robson, Tracy
Salto-Tellez, Manuel
Longley, Daniel B.
Waugh, David J.J.
PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy
title PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy
title_full PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy
title_fullStr PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy
title_full_unstemmed PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy
title_short PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy
title_sort pten deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to iap antagonist/radiation combination therapy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884961/
https://www.ncbi.nlm.nih.gov/pubmed/26799286
http://dx.doi.org/10.18632/oncotarget.6955
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