Cargando…

Neuregulin Promotes Incomplete Autophagy of Prostate Cancer Cells That Is Independent of mTOR Pathway Inhibition

BACKGROUND: Growth factors activating the ErbB receptors have been described in prostate tumors. The androgen dependent prostate cancer cell line, LNCaP, expresses the ErbB-1, ErbB-2 and ErbB-3 receptor tyrosine kinases. Previously, it was demonstrated that NRG activates ErbB-2/ErbB-3 heterodimers t...

Descripción completa

Detalles Bibliográficos
Autores principales: Schmukler, Eran, Shai, Ben, Ehrlich, Marcelo, Pinkas-Kramarski, Ronit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351469/
https://www.ncbi.nlm.nih.gov/pubmed/22606295
http://dx.doi.org/10.1371/journal.pone.0036828
_version_ 1782232775977336832
author Schmukler, Eran
Shai, Ben
Ehrlich, Marcelo
Pinkas-Kramarski, Ronit
author_facet Schmukler, Eran
Shai, Ben
Ehrlich, Marcelo
Pinkas-Kramarski, Ronit
author_sort Schmukler, Eran
collection PubMed
description BACKGROUND: Growth factors activating the ErbB receptors have been described in prostate tumors. The androgen dependent prostate cancer cell line, LNCaP, expresses the ErbB-1, ErbB-2 and ErbB-3 receptor tyrosine kinases. Previously, it was demonstrated that NRG activates ErbB-2/ErbB-3 heterodimers to induce LNCaP cell death, whereas, EGF activates ErbB-1/ErbB-1 or ErbB-1/ErbB-2 dimers to induce cell growth and survival. It was also demonstrated that PI3K inhibitors repressed this cell death suggesting that in androgen deprived LNCaP cells, NRG activates a PI3K-dependent pathway associated with cell death. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we demonstrate that NRG induces autophagy in LNCaP cells, using LC3 as a marker. However, the autophagy induced by NRG may be incomplete since p62 levels elevate. We also demonstrated that NRG- induced autophagy is independent of mammalian target of rapamycin (mTOR) inhibition since NRG induces Akt and S6K activation. Interestingly, inhibition of reactive oxygen species (ROS) by N-acetylcysteine (NAC), inhibited NRG-induced autophagy and cell death. Our study also identified JNK and Beclin 1 as important components in NRG-induced autophagy and cell death. NRG induced elevation in JNK phosphorylation that was inhibited by NAC. Moreover, inhibitor of JNK inhibited NRG-induced autophagy and cell death. Also, in cells overexpressing Bcl-2 or cells expressing sh-RNA against Beclin 1, the effects of NRG, namely induction of autophagy and cell death, were inhibited. CONCLUSIONS/SIGNIFICANCE: Thus, in LNCaP cells, NRG-induces incomplete autophagy and cell death that depend on ROS levels. These effects of NRG are mediated by signaling pathway that activates JNK and Beclin 1, but is independent of mTOR inhibition.
format Online
Article
Text
id pubmed-3351469
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-33514692012-05-17 Neuregulin Promotes Incomplete Autophagy of Prostate Cancer Cells That Is Independent of mTOR Pathway Inhibition Schmukler, Eran Shai, Ben Ehrlich, Marcelo Pinkas-Kramarski, Ronit PLoS One Research Article BACKGROUND: Growth factors activating the ErbB receptors have been described in prostate tumors. The androgen dependent prostate cancer cell line, LNCaP, expresses the ErbB-1, ErbB-2 and ErbB-3 receptor tyrosine kinases. Previously, it was demonstrated that NRG activates ErbB-2/ErbB-3 heterodimers to induce LNCaP cell death, whereas, EGF activates ErbB-1/ErbB-1 or ErbB-1/ErbB-2 dimers to induce cell growth and survival. It was also demonstrated that PI3K inhibitors repressed this cell death suggesting that in androgen deprived LNCaP cells, NRG activates a PI3K-dependent pathway associated with cell death. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we demonstrate that NRG induces autophagy in LNCaP cells, using LC3 as a marker. However, the autophagy induced by NRG may be incomplete since p62 levels elevate. We also demonstrated that NRG- induced autophagy is independent of mammalian target of rapamycin (mTOR) inhibition since NRG induces Akt and S6K activation. Interestingly, inhibition of reactive oxygen species (ROS) by N-acetylcysteine (NAC), inhibited NRG-induced autophagy and cell death. Our study also identified JNK and Beclin 1 as important components in NRG-induced autophagy and cell death. NRG induced elevation in JNK phosphorylation that was inhibited by NAC. Moreover, inhibitor of JNK inhibited NRG-induced autophagy and cell death. Also, in cells overexpressing Bcl-2 or cells expressing sh-RNA against Beclin 1, the effects of NRG, namely induction of autophagy and cell death, were inhibited. CONCLUSIONS/SIGNIFICANCE: Thus, in LNCaP cells, NRG-induces incomplete autophagy and cell death that depend on ROS levels. These effects of NRG are mediated by signaling pathway that activates JNK and Beclin 1, but is independent of mTOR inhibition. Public Library of Science 2012-05-14 /pmc/articles/PMC3351469/ /pubmed/22606295 http://dx.doi.org/10.1371/journal.pone.0036828 Text en Schmukler 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
Schmukler, Eran
Shai, Ben
Ehrlich, Marcelo
Pinkas-Kramarski, Ronit
Neuregulin Promotes Incomplete Autophagy of Prostate Cancer Cells That Is Independent of mTOR Pathway Inhibition
title Neuregulin Promotes Incomplete Autophagy of Prostate Cancer Cells That Is Independent of mTOR Pathway Inhibition
title_full Neuregulin Promotes Incomplete Autophagy of Prostate Cancer Cells That Is Independent of mTOR Pathway Inhibition
title_fullStr Neuregulin Promotes Incomplete Autophagy of Prostate Cancer Cells That Is Independent of mTOR Pathway Inhibition
title_full_unstemmed Neuregulin Promotes Incomplete Autophagy of Prostate Cancer Cells That Is Independent of mTOR Pathway Inhibition
title_short Neuregulin Promotes Incomplete Autophagy of Prostate Cancer Cells That Is Independent of mTOR Pathway Inhibition
title_sort neuregulin promotes incomplete autophagy of prostate cancer cells that is independent of mtor pathway inhibition
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351469/
https://www.ncbi.nlm.nih.gov/pubmed/22606295
http://dx.doi.org/10.1371/journal.pone.0036828
work_keys_str_mv AT schmuklereran neuregulinpromotesincompleteautophagyofprostatecancercellsthatisindependentofmtorpathwayinhibition
AT shaiben neuregulinpromotesincompleteautophagyofprostatecancercellsthatisindependentofmtorpathwayinhibition
AT ehrlichmarcelo neuregulinpromotesincompleteautophagyofprostatecancercellsthatisindependentofmtorpathwayinhibition
AT pinkaskramarskironit neuregulinpromotesincompleteautophagyofprostatecancercellsthatisindependentofmtorpathwayinhibition