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RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer
The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabeti...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10351154/ https://www.ncbi.nlm.nih.gov/pubmed/37461077 http://dx.doi.org/10.1186/s13058-023-01686-5 |
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author | Muoio, M. G. Pellegrino, M. Rapicavoli, V. Talia, M. Scavo, G. Sergi, V. Vella, V. Pettinato, S. Galasso, M. G. Lappano, R. Scordamaglia, D. Cirillo, F. Pulvirenti, A. Rigiracciolo, D. C. Maggiolini, M. Belfiore, A. De Francesco, E. M. |
author_facet | Muoio, M. G. Pellegrino, M. Rapicavoli, V. Talia, M. Scavo, G. Sergi, V. Vella, V. Pettinato, S. Galasso, M. G. Lappano, R. Scordamaglia, D. Cirillo, F. Pulvirenti, A. Rigiracciolo, D. C. Maggiolini, M. Belfiore, A. De Francesco, E. M. |
author_sort | Muoio, M. G. |
collection | PubMed |
description | The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-023-01686-5. |
format | Online Article Text |
id | pubmed-10351154 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-103511542023-07-18 RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer Muoio, M. G. Pellegrino, M. Rapicavoli, V. Talia, M. Scavo, G. Sergi, V. Vella, V. Pettinato, S. Galasso, M. G. Lappano, R. Scordamaglia, D. Cirillo, F. Pulvirenti, A. Rigiracciolo, D. C. Maggiolini, M. Belfiore, A. De Francesco, E. M. Breast Cancer Res Research The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-023-01686-5. BioMed Central 2023-07-17 2023 /pmc/articles/PMC10351154/ /pubmed/37461077 http://dx.doi.org/10.1186/s13058-023-01686-5 Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Muoio, M. G. Pellegrino, M. Rapicavoli, V. Talia, M. Scavo, G. Sergi, V. Vella, V. Pettinato, S. Galasso, M. G. Lappano, R. Scordamaglia, D. Cirillo, F. Pulvirenti, A. Rigiracciolo, D. C. Maggiolini, M. Belfiore, A. De Francesco, E. M. RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer |
title | RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer |
title_full | RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer |
title_fullStr | RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer |
title_full_unstemmed | RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer |
title_short | RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer |
title_sort | rage inhibition blunts insulin-induced oncogenic signals in breast cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10351154/ https://www.ncbi.nlm.nih.gov/pubmed/37461077 http://dx.doi.org/10.1186/s13058-023-01686-5 |
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