Cargando…

Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling()

Platelets have been long postulated to play a critical role in the pathogenesis of prostate cancer, although relatively little is known regarding the precise mechanisms involved. Androgen deprivation therapy (ADT) for prostate cancer eventually fails with relapse occurring in the form of castration-...

Descripción completa

Detalles Bibliográficos
Autores principales: Zaslavsky, Alexander B., Gloeckner-Kalousek, Audrey, Adams, Mackenzie, Putluri, Nagireddy, Venghatakrishnan, Harene, Li, Hangwen, Morgan, Todd M., Feng, Felix Y., Tewari, Muneesh, Sreekumar, Arun, Palapattu, Ganesh S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719002/
https://www.ncbi.nlm.nih.gov/pubmed/26152357
http://dx.doi.org/10.1016/j.neo.2015.05.003
_version_ 1782410875043315712
author Zaslavsky, Alexander B.
Gloeckner-Kalousek, Audrey
Adams, Mackenzie
Putluri, Nagireddy
Venghatakrishnan, Harene
Li, Hangwen
Morgan, Todd M.
Feng, Felix Y.
Tewari, Muneesh
Sreekumar, Arun
Palapattu, Ganesh S.
author_facet Zaslavsky, Alexander B.
Gloeckner-Kalousek, Audrey
Adams, Mackenzie
Putluri, Nagireddy
Venghatakrishnan, Harene
Li, Hangwen
Morgan, Todd M.
Feng, Felix Y.
Tewari, Muneesh
Sreekumar, Arun
Palapattu, Ganesh S.
author_sort Zaslavsky, Alexander B.
collection PubMed
description Platelets have been long postulated to play a critical role in the pathogenesis of prostate cancer, although relatively little is known regarding the precise mechanisms involved. Androgen deprivation therapy (ADT) for prostate cancer eventually fails with relapse occurring in the form of castration-resistant prostate cancer (CRPC). CRPC tumors typically overexpress androgen receptor (AR), demonstrating continued dependence upon AR signaling. Platelets have been previously demonstrated to contain androgens, and we sought to explore the contribution of platelet-derived androgens in CRPC. In this study, we examined the role of platelet-derived androgens in vitro using platelets from men with CRPC, men with high-risk prostate cancer, and healthy male donors. A series of in vitro assays was performed to elucidate the impact of platelet-derived androgens on androgen-sensitive prostate tumor cells. By examining platelet-derived androgen effects on AR signaling in prostate tumor cells, we found that platelets, from men with CRPC and on ADT, strongly induce AR target genes and tumor cell proliferation. Moreover, we show a fully intact testosterone (T) biosynthetic pathway within platelets from its precursor cholesterol and demonstrate that platelets of CRPC patients with ADT resistance are able to generate T. Overall, our findings reveal an unknown capacity of platelets to synthesize T at functionally relevant levels in patients with lethal prostate cancer. Importantly, it suggests a novel paracrine mechanism of T production that may act to sustain CRPC state and potentiate therapeutic resistance.
format Online
Article
Text
id pubmed-4719002
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Neoplasia Press
record_format MEDLINE/PubMed
spelling pubmed-47190022016-02-19 Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling() Zaslavsky, Alexander B. Gloeckner-Kalousek, Audrey Adams, Mackenzie Putluri, Nagireddy Venghatakrishnan, Harene Li, Hangwen Morgan, Todd M. Feng, Felix Y. Tewari, Muneesh Sreekumar, Arun Palapattu, Ganesh S. Neoplasia Article Platelets have been long postulated to play a critical role in the pathogenesis of prostate cancer, although relatively little is known regarding the precise mechanisms involved. Androgen deprivation therapy (ADT) for prostate cancer eventually fails with relapse occurring in the form of castration-resistant prostate cancer (CRPC). CRPC tumors typically overexpress androgen receptor (AR), demonstrating continued dependence upon AR signaling. Platelets have been previously demonstrated to contain androgens, and we sought to explore the contribution of platelet-derived androgens in CRPC. In this study, we examined the role of platelet-derived androgens in vitro using platelets from men with CRPC, men with high-risk prostate cancer, and healthy male donors. A series of in vitro assays was performed to elucidate the impact of platelet-derived androgens on androgen-sensitive prostate tumor cells. By examining platelet-derived androgen effects on AR signaling in prostate tumor cells, we found that platelets, from men with CRPC and on ADT, strongly induce AR target genes and tumor cell proliferation. Moreover, we show a fully intact testosterone (T) biosynthetic pathway within platelets from its precursor cholesterol and demonstrate that platelets of CRPC patients with ADT resistance are able to generate T. Overall, our findings reveal an unknown capacity of platelets to synthesize T at functionally relevant levels in patients with lethal prostate cancer. Importantly, it suggests a novel paracrine mechanism of T production that may act to sustain CRPC state and potentiate therapeutic resistance. Neoplasia Press 2015-07-04 /pmc/articles/PMC4719002/ /pubmed/26152357 http://dx.doi.org/10.1016/j.neo.2015.05.003 Text en © 2014 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Zaslavsky, Alexander B.
Gloeckner-Kalousek, Audrey
Adams, Mackenzie
Putluri, Nagireddy
Venghatakrishnan, Harene
Li, Hangwen
Morgan, Todd M.
Feng, Felix Y.
Tewari, Muneesh
Sreekumar, Arun
Palapattu, Ganesh S.
Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling()
title Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling()
title_full Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling()
title_fullStr Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling()
title_full_unstemmed Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling()
title_short Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling()
title_sort platelet-synthesized testosterone in men with prostate cancer induces androgen receptor signaling()
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719002/
https://www.ncbi.nlm.nih.gov/pubmed/26152357
http://dx.doi.org/10.1016/j.neo.2015.05.003
work_keys_str_mv AT zaslavskyalexanderb plateletsynthesizedtestosteroneinmenwithprostatecancerinducesandrogenreceptorsignaling
AT gloecknerkalousekaudrey plateletsynthesizedtestosteroneinmenwithprostatecancerinducesandrogenreceptorsignaling
AT adamsmackenzie plateletsynthesizedtestosteroneinmenwithprostatecancerinducesandrogenreceptorsignaling
AT putlurinagireddy plateletsynthesizedtestosteroneinmenwithprostatecancerinducesandrogenreceptorsignaling
AT venghatakrishnanharene plateletsynthesizedtestosteroneinmenwithprostatecancerinducesandrogenreceptorsignaling
AT lihangwen plateletsynthesizedtestosteroneinmenwithprostatecancerinducesandrogenreceptorsignaling
AT morgantoddm plateletsynthesizedtestosteroneinmenwithprostatecancerinducesandrogenreceptorsignaling
AT fengfelixy plateletsynthesizedtestosteroneinmenwithprostatecancerinducesandrogenreceptorsignaling
AT tewarimuneesh plateletsynthesizedtestosteroneinmenwithprostatecancerinducesandrogenreceptorsignaling
AT sreekumararun plateletsynthesizedtestosteroneinmenwithprostatecancerinducesandrogenreceptorsignaling
AT palapattuganeshs plateletsynthesizedtestosteroneinmenwithprostatecancerinducesandrogenreceptorsignaling