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Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer
Although the antitumor role of metformin has been widely reported, the molecular mechanism of this biguanide agent in the inhibition of tumor progression remains unclear. Here, we identified miR-708-5p as a novel target of metformin in prostate cancer cells. Metformin promotes increased expression o...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491613/ https://www.ncbi.nlm.nih.gov/pubmed/26075749 http://dx.doi.org/10.1038/oncsis.2015.18 |
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author | Yang, J Wei, J Wu, Y Wang, Z Guo, Y Lee, P Li, X |
author_facet | Yang, J Wei, J Wu, Y Wang, Z Guo, Y Lee, P Li, X |
author_sort | Yang, J |
collection | PubMed |
description | Although the antitumor role of metformin has been widely reported, the molecular mechanism of this biguanide agent in the inhibition of tumor progression remains unclear. Here, we identified miR-708-5p as a novel target of metformin in prostate cancer cells. Metformin promotes increased expression of miR-708-5p, leading to suppression of endoplasmic reticulum (ER) membrane protein neuronatin (NNAT) expression and subsequently induces apoptosis of prostate cancer cells through the ER stress pathway. Further, miR-708-5p-induced knockdown of NNAT is associated with downregulated intracellular calcium levels and induced malformation of ER-ribosome structure revealed by electronic microscopy. Meanwhile, the unfolded protein response regulator CHOP, p-eIF2α, calreticulin, GRP78 and ATP2A1, all of which are also considered as ER stress markers, are upregulated by metformin and miR-708-5p. Taken together, our findings clearly demonstrate that metformin stimulates increased expression of miR-708-5p to target the NNAT-mediated response to ER stress and apoptosis. This novel regulatory mechanism of metformin in prostate cancer cells not only advances our knowledge on the molecular mechanism of metformin but also provides a promising therapeutic strategy by targeting miR-708-5p and NNAT for prostate cancer treatment. |
format | Online Article Text |
id | pubmed-4491613 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-44916132015-07-17 Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer Yang, J Wei, J Wu, Y Wang, Z Guo, Y Lee, P Li, X Oncogenesis Original Article Although the antitumor role of metformin has been widely reported, the molecular mechanism of this biguanide agent in the inhibition of tumor progression remains unclear. Here, we identified miR-708-5p as a novel target of metformin in prostate cancer cells. Metformin promotes increased expression of miR-708-5p, leading to suppression of endoplasmic reticulum (ER) membrane protein neuronatin (NNAT) expression and subsequently induces apoptosis of prostate cancer cells through the ER stress pathway. Further, miR-708-5p-induced knockdown of NNAT is associated with downregulated intracellular calcium levels and induced malformation of ER-ribosome structure revealed by electronic microscopy. Meanwhile, the unfolded protein response regulator CHOP, p-eIF2α, calreticulin, GRP78 and ATP2A1, all of which are also considered as ER stress markers, are upregulated by metformin and miR-708-5p. Taken together, our findings clearly demonstrate that metformin stimulates increased expression of miR-708-5p to target the NNAT-mediated response to ER stress and apoptosis. This novel regulatory mechanism of metformin in prostate cancer cells not only advances our knowledge on the molecular mechanism of metformin but also provides a promising therapeutic strategy by targeting miR-708-5p and NNAT for prostate cancer treatment. Nature Publishing Group 2015-06 2015-06-15 /pmc/articles/PMC4491613/ /pubmed/26075749 http://dx.doi.org/10.1038/oncsis.2015.18 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Yang, J Wei, J Wu, Y Wang, Z Guo, Y Lee, P Li, X Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer |
title | Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer |
title_full | Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer |
title_fullStr | Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer |
title_full_unstemmed | Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer |
title_short | Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer |
title_sort | metformin induces er stress-dependent apoptosis through mir-708-5p/nnat pathway in prostate cancer |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491613/ https://www.ncbi.nlm.nih.gov/pubmed/26075749 http://dx.doi.org/10.1038/oncsis.2015.18 |
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