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Stim and Orai mediate constitutive Ca(2+) entry and control endoplasmic reticulum Ca(2+) refilling in primary cultures of colorectal carcinoma cells

Store-operated Ca(2+) entry (SOCE) provides a major Ca(2+) entry route in cancer cells. SOCE is mediated by the assembly of Stim and Orai proteins at endoplasmic reticulum (ER)-plasma membrane junctions upon depletion of the ER Ca(2+) store. Additionally, Stim and Orai proteins underpin constitutive...

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Autores principales: Zuccolo, Estella, Laforenza, Umberto, Ferulli, Federica, Pellavio, Giorgia, Scarpellino, Giorgia, Tanzi, Matteo, Turin, Ilaria, Faris, Pawan, Lucariello, Angela, Maestri, Marcello, Kheder, Dlzar Ali, Guerra, Germano, Pedrazzoli, Paolo, Montagna, Daniela, Moccia, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089563/
https://www.ncbi.nlm.nih.gov/pubmed/30123430
http://dx.doi.org/10.18632/oncotarget.25785
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author Zuccolo, Estella
Laforenza, Umberto
Ferulli, Federica
Pellavio, Giorgia
Scarpellino, Giorgia
Tanzi, Matteo
Turin, Ilaria
Faris, Pawan
Lucariello, Angela
Maestri, Marcello
Kheder, Dlzar Ali
Guerra, Germano
Pedrazzoli, Paolo
Montagna, Daniela
Moccia, Francesco
author_facet Zuccolo, Estella
Laforenza, Umberto
Ferulli, Federica
Pellavio, Giorgia
Scarpellino, Giorgia
Tanzi, Matteo
Turin, Ilaria
Faris, Pawan
Lucariello, Angela
Maestri, Marcello
Kheder, Dlzar Ali
Guerra, Germano
Pedrazzoli, Paolo
Montagna, Daniela
Moccia, Francesco
author_sort Zuccolo, Estella
collection PubMed
description Store-operated Ca(2+) entry (SOCE) provides a major Ca(2+) entry route in cancer cells. SOCE is mediated by the assembly of Stim and Orai proteins at endoplasmic reticulum (ER)-plasma membrane junctions upon depletion of the ER Ca(2+) store. Additionally, Stim and Orai proteins underpin constitutive Ca(2+) entry in a growing number of cancer cell types due to the partial depletion of their ER Ca(2+) reservoir. Herein, we investigated for the first time the structure and function of SOCE in primary cultures of colorectal carcinoma (CRC) established from primary tumor (pCRC) and metastatic lesions (mCRC) of human subjects. Stim1-2 and Orai1-3 transcripts were equally expressed in pCRC and mCRC cells, although Stim1 and Orai3 proteins were up-regulated in mCRC cells. The Mn(2+)-quenching technique revealed that constitutive Ca2(+) entry was significantly enhanced in pCRC cells and was inhibited by the pharmacological and genetic blockade of Stim1, Stim2, Orai1 and Orai3. The larger resting Ca(2+) influx in pCRC was associated to their lower ER Ca(2+) content as compared to mCRC cells. Pharmacological and genetic blockade of Stim1, Stim2, Orai1 and Orai3 prevented ER-dependent Ca(2+) release, thereby suggesting that constitutive SOCE maintains ER Ca(2+) levels. Nevertheless, pharmacological and genetic blockade of Stim1, Stim2, Orai1 and Orai3 did not affect CRC cell proliferation and migration. These data provide the first evidence that Stim and Orai proteins mediate constitutive Ca(2+) entry and replenish ER with Ca(2+) in primary cultures of CRC cells. However, SOCE is not a promising target to design alternative therapies for CRC.
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spelling pubmed-60895632018-08-17 Stim and Orai mediate constitutive Ca(2+) entry and control endoplasmic reticulum Ca(2+) refilling in primary cultures of colorectal carcinoma cells Zuccolo, Estella Laforenza, Umberto Ferulli, Federica Pellavio, Giorgia Scarpellino, Giorgia Tanzi, Matteo Turin, Ilaria Faris, Pawan Lucariello, Angela Maestri, Marcello Kheder, Dlzar Ali Guerra, Germano Pedrazzoli, Paolo Montagna, Daniela Moccia, Francesco Oncotarget Research Paper Store-operated Ca(2+) entry (SOCE) provides a major Ca(2+) entry route in cancer cells. SOCE is mediated by the assembly of Stim and Orai proteins at endoplasmic reticulum (ER)-plasma membrane junctions upon depletion of the ER Ca(2+) store. Additionally, Stim and Orai proteins underpin constitutive Ca(2+) entry in a growing number of cancer cell types due to the partial depletion of their ER Ca(2+) reservoir. Herein, we investigated for the first time the structure and function of SOCE in primary cultures of colorectal carcinoma (CRC) established from primary tumor (pCRC) and metastatic lesions (mCRC) of human subjects. Stim1-2 and Orai1-3 transcripts were equally expressed in pCRC and mCRC cells, although Stim1 and Orai3 proteins were up-regulated in mCRC cells. The Mn(2+)-quenching technique revealed that constitutive Ca2(+) entry was significantly enhanced in pCRC cells and was inhibited by the pharmacological and genetic blockade of Stim1, Stim2, Orai1 and Orai3. The larger resting Ca(2+) influx in pCRC was associated to their lower ER Ca(2+) content as compared to mCRC cells. Pharmacological and genetic blockade of Stim1, Stim2, Orai1 and Orai3 prevented ER-dependent Ca(2+) release, thereby suggesting that constitutive SOCE maintains ER Ca(2+) levels. Nevertheless, pharmacological and genetic blockade of Stim1, Stim2, Orai1 and Orai3 did not affect CRC cell proliferation and migration. These data provide the first evidence that Stim and Orai proteins mediate constitutive Ca(2+) entry and replenish ER with Ca(2+) in primary cultures of CRC cells. However, SOCE is not a promising target to design alternative therapies for CRC. Impact Journals LLC 2018-07-24 /pmc/articles/PMC6089563/ /pubmed/30123430 http://dx.doi.org/10.18632/oncotarget.25785 Text en Copyright: © 2018 Zuccolo et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Zuccolo, Estella
Laforenza, Umberto
Ferulli, Federica
Pellavio, Giorgia
Scarpellino, Giorgia
Tanzi, Matteo
Turin, Ilaria
Faris, Pawan
Lucariello, Angela
Maestri, Marcello
Kheder, Dlzar Ali
Guerra, Germano
Pedrazzoli, Paolo
Montagna, Daniela
Moccia, Francesco
Stim and Orai mediate constitutive Ca(2+) entry and control endoplasmic reticulum Ca(2+) refilling in primary cultures of colorectal carcinoma cells
title Stim and Orai mediate constitutive Ca(2+) entry and control endoplasmic reticulum Ca(2+) refilling in primary cultures of colorectal carcinoma cells
title_full Stim and Orai mediate constitutive Ca(2+) entry and control endoplasmic reticulum Ca(2+) refilling in primary cultures of colorectal carcinoma cells
title_fullStr Stim and Orai mediate constitutive Ca(2+) entry and control endoplasmic reticulum Ca(2+) refilling in primary cultures of colorectal carcinoma cells
title_full_unstemmed Stim and Orai mediate constitutive Ca(2+) entry and control endoplasmic reticulum Ca(2+) refilling in primary cultures of colorectal carcinoma cells
title_short Stim and Orai mediate constitutive Ca(2+) entry and control endoplasmic reticulum Ca(2+) refilling in primary cultures of colorectal carcinoma cells
title_sort stim and orai mediate constitutive ca(2+) entry and control endoplasmic reticulum ca(2+) refilling in primary cultures of colorectal carcinoma cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089563/
https://www.ncbi.nlm.nih.gov/pubmed/30123430
http://dx.doi.org/10.18632/oncotarget.25785
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