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Pan-Sigma Receptor Modulator RC-106 Induces Terminal Unfolded Protein Response In In Vitro Pancreatic Cancer Model

Pancreatic cancer (PC) remains one of the most lethal cancers worldwide. Sigma receptors (SRs) have been proposed as cancer therapeutic targets. Their main localization suggests they play a potential role in ER stress and in the triggering of the unfolded protein response (UPR). Here, we investigate...

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Autores principales: Cortesi, Michela, Zamagni, Alice, Pignatta, Sara, Zanoni, Michele, Arienti, Chiara, Rossi, Daniela, Collina, Simona, Tesei, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734580/
https://www.ncbi.nlm.nih.gov/pubmed/33260926
http://dx.doi.org/10.3390/ijms21239012
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author Cortesi, Michela
Zamagni, Alice
Pignatta, Sara
Zanoni, Michele
Arienti, Chiara
Rossi, Daniela
Collina, Simona
Tesei, Anna
author_facet Cortesi, Michela
Zamagni, Alice
Pignatta, Sara
Zanoni, Michele
Arienti, Chiara
Rossi, Daniela
Collina, Simona
Tesei, Anna
author_sort Cortesi, Michela
collection PubMed
description Pancreatic cancer (PC) remains one of the most lethal cancers worldwide. Sigma receptors (SRs) have been proposed as cancer therapeutic targets. Their main localization suggests they play a potential role in ER stress and in the triggering of the unfolded protein response (UPR). Here, we investigated the mechanisms of action of RC-106, a novel pan-SR modulator, to characterize therapeutically exploitable role of SRs in tumors. Two PC cell lines were used in all the experiments. Terminal UPR activation was evaluated by quantifying BiP, ATF4 and CHOP by Real-Time qRT-PCR, Western Blot, immunofluorescence and confocal microscopy. Cell death was studied by flow cytometry. Post-transcriptional gene silencing was performed to study the interactions between SRs and UPR key proteins. RC-106 activated ER stress sensors in a dose- and time-dependent manner. It also induced ROS production accordingly with ATF4 upregulation at the same time reducing cell viability of both cell lines tested. Moreover, RC-106 exerted its effect through the induction of the terminal UPR, as shown by the activation of some of the main transducers of this pathway. Post-transcriptional silencing studies confirmed the connection between SRs and these key proteins. Overall, our data highlighted a key role of SRs in the activation of the terminal UPR pathway, thus indicating pan-SR ligands as candidates for targeting the UPR in pancreatic cancer.
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spelling pubmed-77345802020-12-15 Pan-Sigma Receptor Modulator RC-106 Induces Terminal Unfolded Protein Response In In Vitro Pancreatic Cancer Model Cortesi, Michela Zamagni, Alice Pignatta, Sara Zanoni, Michele Arienti, Chiara Rossi, Daniela Collina, Simona Tesei, Anna Int J Mol Sci Article Pancreatic cancer (PC) remains one of the most lethal cancers worldwide. Sigma receptors (SRs) have been proposed as cancer therapeutic targets. Their main localization suggests they play a potential role in ER stress and in the triggering of the unfolded protein response (UPR). Here, we investigated the mechanisms of action of RC-106, a novel pan-SR modulator, to characterize therapeutically exploitable role of SRs in tumors. Two PC cell lines were used in all the experiments. Terminal UPR activation was evaluated by quantifying BiP, ATF4 and CHOP by Real-Time qRT-PCR, Western Blot, immunofluorescence and confocal microscopy. Cell death was studied by flow cytometry. Post-transcriptional gene silencing was performed to study the interactions between SRs and UPR key proteins. RC-106 activated ER stress sensors in a dose- and time-dependent manner. It also induced ROS production accordingly with ATF4 upregulation at the same time reducing cell viability of both cell lines tested. Moreover, RC-106 exerted its effect through the induction of the terminal UPR, as shown by the activation of some of the main transducers of this pathway. Post-transcriptional silencing studies confirmed the connection between SRs and these key proteins. Overall, our data highlighted a key role of SRs in the activation of the terminal UPR pathway, thus indicating pan-SR ligands as candidates for targeting the UPR in pancreatic cancer. MDPI 2020-11-27 /pmc/articles/PMC7734580/ /pubmed/33260926 http://dx.doi.org/10.3390/ijms21239012 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cortesi, Michela
Zamagni, Alice
Pignatta, Sara
Zanoni, Michele
Arienti, Chiara
Rossi, Daniela
Collina, Simona
Tesei, Anna
Pan-Sigma Receptor Modulator RC-106 Induces Terminal Unfolded Protein Response In In Vitro Pancreatic Cancer Model
title Pan-Sigma Receptor Modulator RC-106 Induces Terminal Unfolded Protein Response In In Vitro Pancreatic Cancer Model
title_full Pan-Sigma Receptor Modulator RC-106 Induces Terminal Unfolded Protein Response In In Vitro Pancreatic Cancer Model
title_fullStr Pan-Sigma Receptor Modulator RC-106 Induces Terminal Unfolded Protein Response In In Vitro Pancreatic Cancer Model
title_full_unstemmed Pan-Sigma Receptor Modulator RC-106 Induces Terminal Unfolded Protein Response In In Vitro Pancreatic Cancer Model
title_short Pan-Sigma Receptor Modulator RC-106 Induces Terminal Unfolded Protein Response In In Vitro Pancreatic Cancer Model
title_sort pan-sigma receptor modulator rc-106 induces terminal unfolded protein response in in vitro pancreatic cancer model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734580/
https://www.ncbi.nlm.nih.gov/pubmed/33260926
http://dx.doi.org/10.3390/ijms21239012
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