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Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid
Calcium ions (Ca(2+)) play important and diverse roles in the regulation of autophagy, cell death and differentiation. Here, we investigated the impact of Ca(2+) in regulating acute promyelocytic leukemia (APL) cell fate in response to the anti-cancer agent all-trans retinoic acid (ATRA). We observe...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699360/ https://www.ncbi.nlm.nih.gov/pubmed/34943872 http://dx.doi.org/10.3390/cells10123364 |
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author | Merhi, Faten Alvarez-Valadez, Karla Trepiana, Jenifer Lescoat, Claire Groppi, Alexis Dupuy, Jean-William Soubeyran, Pierre Kroemer, Guido Vacher, Pierre Djavaheri-Mergny, Mojgan |
author_facet | Merhi, Faten Alvarez-Valadez, Karla Trepiana, Jenifer Lescoat, Claire Groppi, Alexis Dupuy, Jean-William Soubeyran, Pierre Kroemer, Guido Vacher, Pierre Djavaheri-Mergny, Mojgan |
author_sort | Merhi, Faten |
collection | PubMed |
description | Calcium ions (Ca(2+)) play important and diverse roles in the regulation of autophagy, cell death and differentiation. Here, we investigated the impact of Ca(2+) in regulating acute promyelocytic leukemia (APL) cell fate in response to the anti-cancer agent all-trans retinoic acid (ATRA). We observed that ATRA promotes calcium entry through store-operated calcium (SOC) channels into acute promyelocytic leukemia (APL) cells. This response is associated with changes in the expression profiles of ORAI1 and STIM1, two proteins involved in SOC channels activation, as well as with a significant upregulation of several key proteins associated to calcium signaling. Moreover, ATRA treatment of APL cells led to a significant activation of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) and its downstream effector AMP-activated protein kinase (AMPK), linking Ca(2+) signaling to autophagy. Pharmacological inhibition of SOC channels and CAMKK2 enhanced ATRA-induced cell differentiation and death. Altogether, our results unravel an ATRA-elicited signaling pathway that involves SOC channels/CAMKK2 activation, induction of autophagy, inhibition of cellular differentiation and suppression of cell death. We suggest that SOC channels and CAMKK2 may constitute novel drug targets for potentiating the anti-cancer effect of ATRA in APL patients. |
format | Online Article Text |
id | pubmed-8699360 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-86993602021-12-24 Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid Merhi, Faten Alvarez-Valadez, Karla Trepiana, Jenifer Lescoat, Claire Groppi, Alexis Dupuy, Jean-William Soubeyran, Pierre Kroemer, Guido Vacher, Pierre Djavaheri-Mergny, Mojgan Cells Article Calcium ions (Ca(2+)) play important and diverse roles in the regulation of autophagy, cell death and differentiation. Here, we investigated the impact of Ca(2+) in regulating acute promyelocytic leukemia (APL) cell fate in response to the anti-cancer agent all-trans retinoic acid (ATRA). We observed that ATRA promotes calcium entry through store-operated calcium (SOC) channels into acute promyelocytic leukemia (APL) cells. This response is associated with changes in the expression profiles of ORAI1 and STIM1, two proteins involved in SOC channels activation, as well as with a significant upregulation of several key proteins associated to calcium signaling. Moreover, ATRA treatment of APL cells led to a significant activation of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) and its downstream effector AMP-activated protein kinase (AMPK), linking Ca(2+) signaling to autophagy. Pharmacological inhibition of SOC channels and CAMKK2 enhanced ATRA-induced cell differentiation and death. Altogether, our results unravel an ATRA-elicited signaling pathway that involves SOC channels/CAMKK2 activation, induction of autophagy, inhibition of cellular differentiation and suppression of cell death. We suggest that SOC channels and CAMKK2 may constitute novel drug targets for potentiating the anti-cancer effect of ATRA in APL patients. MDPI 2021-11-30 /pmc/articles/PMC8699360/ /pubmed/34943872 http://dx.doi.org/10.3390/cells10123364 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Merhi, Faten Alvarez-Valadez, Karla Trepiana, Jenifer Lescoat, Claire Groppi, Alexis Dupuy, Jean-William Soubeyran, Pierre Kroemer, Guido Vacher, Pierre Djavaheri-Mergny, Mojgan Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid |
title | Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid |
title_full | Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid |
title_fullStr | Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid |
title_full_unstemmed | Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid |
title_short | Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid |
title_sort | targeting camkk2 and soc channels as a novel therapeutic approach for sensitizing acute promyelocytic leukemia cells to all-trans retinoic acid |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699360/ https://www.ncbi.nlm.nih.gov/pubmed/34943872 http://dx.doi.org/10.3390/cells10123364 |
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