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Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis
BACKGROUND: We and others have extensively investigated the role of PARP-1 in cell growth and demise in response to pathophysiological cues. Most of the clinical trials on PARP inhibitors are targeting primarily estrogen receptor (ER) negative cancers with BRCA-deficiency. It is surprising that the...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504350/ https://www.ncbi.nlm.nih.gov/pubmed/26183824 http://dx.doi.org/10.1186/s12967-015-0589-7 |
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author | Kim, Hogyoung Tarhuni, Abdelmetalab Abd Elmageed, Zakaria Y Boulares, A Hamid |
author_facet | Kim, Hogyoung Tarhuni, Abdelmetalab Abd Elmageed, Zakaria Y Boulares, A Hamid |
author_sort | Kim, Hogyoung |
collection | PubMed |
description | BACKGROUND: We and others have extensively investigated the role of PARP-1 in cell growth and demise in response to pathophysiological cues. Most of the clinical trials on PARP inhibitors are targeting primarily estrogen receptor (ER) negative cancers with BRCA-deficiency. It is surprising that the role of the enzyme has yet to be investigated in ER-mediated cell growth. It is noteworthy that ER is expressed in the majority of breast cancers. We recently showed that the scaffolding protein PDZK1 is critical for 17β-estradiol (E(2))-induced growth of breast cancer cells. We demonstrated that E(2)-induced PDZK1 expression is indirectly regulated by ER and requires IGF-1 receptor (IGF-1R). METHODS: The breast cancer cell lines MCF-7 and BT474 were used as ER(+) cell culture models. Thieno[2,3-c]isoquinolin-5-one (TIQ-A) and olaparib (AZD2281) were used as potent inhibitors of PARP. PARP-1 knockdown by shRNA was used to show specificity of the effects to PARP-1. RESULTS: In this study, we aimed to determine the effect of PARP inhibition on estrogen-induced growth of breast cancer cells and examine whether the potential effect is linked to PDZK1 and IGF-1R expression. Our results show that PARP inhibition pharmacologically by TIQ-A or olaparib or by PARP-1 knockdown blocked E(2)-dependent growth of MCF-7 cells. Such inhibitory effect was also observed in olaparib-treated BT474 cells. The effect of PARP inhibition on cell growth coincided with an efficient reduction in E(2)-induced PDZK1 expression. This effect was accompanied by a similar decrease in the cell cycle protein cyclin D1. PARP appeared to regulate E(2)-induced PDZK1 at the mRNA level. Such regulation may be linked to a modulation of IGF-1R as PARP inhibition pharmacologically or by PARP-1 knockdown efficiently reduced E(2)-induced expression of the receptor at the protein and mRNA levels. CONCLUSIONS: Overall, our results show for the first time that PARP regulates E(2)-mediated cell growth by controlling the ER/IGF-1R/PDZK1 axis. These findings suggest that the relationship between ER, PDZK1, and IGF-1R may be perturbed by blocking PARP function and that PARP inhibitors may be considered in clinical trials on ER(+) cancers. |
format | Online Article Text |
id | pubmed-4504350 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-45043502015-07-17 Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis Kim, Hogyoung Tarhuni, Abdelmetalab Abd Elmageed, Zakaria Y Boulares, A Hamid J Transl Med Research BACKGROUND: We and others have extensively investigated the role of PARP-1 in cell growth and demise in response to pathophysiological cues. Most of the clinical trials on PARP inhibitors are targeting primarily estrogen receptor (ER) negative cancers with BRCA-deficiency. It is surprising that the role of the enzyme has yet to be investigated in ER-mediated cell growth. It is noteworthy that ER is expressed in the majority of breast cancers. We recently showed that the scaffolding protein PDZK1 is critical for 17β-estradiol (E(2))-induced growth of breast cancer cells. We demonstrated that E(2)-induced PDZK1 expression is indirectly regulated by ER and requires IGF-1 receptor (IGF-1R). METHODS: The breast cancer cell lines MCF-7 and BT474 were used as ER(+) cell culture models. Thieno[2,3-c]isoquinolin-5-one (TIQ-A) and olaparib (AZD2281) were used as potent inhibitors of PARP. PARP-1 knockdown by shRNA was used to show specificity of the effects to PARP-1. RESULTS: In this study, we aimed to determine the effect of PARP inhibition on estrogen-induced growth of breast cancer cells and examine whether the potential effect is linked to PDZK1 and IGF-1R expression. Our results show that PARP inhibition pharmacologically by TIQ-A or olaparib or by PARP-1 knockdown blocked E(2)-dependent growth of MCF-7 cells. Such inhibitory effect was also observed in olaparib-treated BT474 cells. The effect of PARP inhibition on cell growth coincided with an efficient reduction in E(2)-induced PDZK1 expression. This effect was accompanied by a similar decrease in the cell cycle protein cyclin D1. PARP appeared to regulate E(2)-induced PDZK1 at the mRNA level. Such regulation may be linked to a modulation of IGF-1R as PARP inhibition pharmacologically or by PARP-1 knockdown efficiently reduced E(2)-induced expression of the receptor at the protein and mRNA levels. CONCLUSIONS: Overall, our results show for the first time that PARP regulates E(2)-mediated cell growth by controlling the ER/IGF-1R/PDZK1 axis. These findings suggest that the relationship between ER, PDZK1, and IGF-1R may be perturbed by blocking PARP function and that PARP inhibitors may be considered in clinical trials on ER(+) cancers. BioMed Central 2015-07-17 /pmc/articles/PMC4504350/ /pubmed/26183824 http://dx.doi.org/10.1186/s12967-015-0589-7 Text en © Kim et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Kim, Hogyoung Tarhuni, Abdelmetalab Abd Elmageed, Zakaria Y Boulares, A Hamid Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis |
title | Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis |
title_full | Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis |
title_fullStr | Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis |
title_full_unstemmed | Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis |
title_short | Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis |
title_sort | poly(adp-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/igf-1 receptor/pdzk1 axis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504350/ https://www.ncbi.nlm.nih.gov/pubmed/26183824 http://dx.doi.org/10.1186/s12967-015-0589-7 |
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