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The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1

Transient receptor potential channel melastatin 2 (TRPM2) is highly expressed in cancer and has an essential function in preserving viability through maintenance of mitochondrial function and antioxidant response. Here, the role of TRPM2 in cell survival was examined in neuroblastoma cells with TRPM...

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Autores principales: Hirschler-Laszkiewicz, Iwona, Festa, Fernanda, Huang, Suming, Moldovan, George-Lucian, Nicolae, Claudia, Dhoonmoon, Ashna, Bao, Lei, Keefer, Kerry, Chen, Shu-jen, Wang, Hong-Gang, Cheung, Joseph Y., Miller, Barbara A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012789/
https://www.ncbi.nlm.nih.gov/pubmed/35428820
http://dx.doi.org/10.1038/s41598-022-10385-8
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author Hirschler-Laszkiewicz, Iwona
Festa, Fernanda
Huang, Suming
Moldovan, George-Lucian
Nicolae, Claudia
Dhoonmoon, Ashna
Bao, Lei
Keefer, Kerry
Chen, Shu-jen
Wang, Hong-Gang
Cheung, Joseph Y.
Miller, Barbara A.
author_facet Hirschler-Laszkiewicz, Iwona
Festa, Fernanda
Huang, Suming
Moldovan, George-Lucian
Nicolae, Claudia
Dhoonmoon, Ashna
Bao, Lei
Keefer, Kerry
Chen, Shu-jen
Wang, Hong-Gang
Cheung, Joseph Y.
Miller, Barbara A.
author_sort Hirschler-Laszkiewicz, Iwona
collection PubMed
description Transient receptor potential channel melastatin 2 (TRPM2) is highly expressed in cancer and has an essential function in preserving viability through maintenance of mitochondrial function and antioxidant response. Here, the role of TRPM2 in cell survival was examined in neuroblastoma cells with TRPM2 deletion with CRISPR technology. Viability was significantly decreased in TRPM2 knockout after doxorubicin treatment. RNA sequence analysis and RT-qPCR revealed reduced RNAs encoding master transcription regulators FOXM1 and E2F1/2 and downstream cell cycle targets including Cyclin B1, CDK1, PLK1, and CKS1. CHIP analysis demonstrated decreased FOXM1 binding to their promoters. Western blotting confirmed decreased expression, and increased expression of CDK inhibitor p21, a CKS1 target. In cells with TRPM2 deletion, cell cycle progression to S and G2/M phases was reduced after treatment with doxorubicin. RNA sequencing also identified decreased DNA repair proteins in cells with TRPM2 deletion after doxorubicin treatment, and DNA damage was increased. Wild type TRPM2, but not Ca(2+)-impermeable mutant E960D, restored live cell number and reconstituted expression of E2F1, FOXM1, and cell cycle/DNA repair proteins. FOXM1 expression alone restored viability. TRPM2 is a potential therapeutic target to reduce tumor proliferation and increase doxorubicin sensitivity through modulation of FOXM1, E2F1, and cell cycle/DNA repair proteins.
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spelling pubmed-90127892022-04-18 The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1 Hirschler-Laszkiewicz, Iwona Festa, Fernanda Huang, Suming Moldovan, George-Lucian Nicolae, Claudia Dhoonmoon, Ashna Bao, Lei Keefer, Kerry Chen, Shu-jen Wang, Hong-Gang Cheung, Joseph Y. Miller, Barbara A. Sci Rep Article Transient receptor potential channel melastatin 2 (TRPM2) is highly expressed in cancer and has an essential function in preserving viability through maintenance of mitochondrial function and antioxidant response. Here, the role of TRPM2 in cell survival was examined in neuroblastoma cells with TRPM2 deletion with CRISPR technology. Viability was significantly decreased in TRPM2 knockout after doxorubicin treatment. RNA sequence analysis and RT-qPCR revealed reduced RNAs encoding master transcription regulators FOXM1 and E2F1/2 and downstream cell cycle targets including Cyclin B1, CDK1, PLK1, and CKS1. CHIP analysis demonstrated decreased FOXM1 binding to their promoters. Western blotting confirmed decreased expression, and increased expression of CDK inhibitor p21, a CKS1 target. In cells with TRPM2 deletion, cell cycle progression to S and G2/M phases was reduced after treatment with doxorubicin. RNA sequencing also identified decreased DNA repair proteins in cells with TRPM2 deletion after doxorubicin treatment, and DNA damage was increased. Wild type TRPM2, but not Ca(2+)-impermeable mutant E960D, restored live cell number and reconstituted expression of E2F1, FOXM1, and cell cycle/DNA repair proteins. FOXM1 expression alone restored viability. TRPM2 is a potential therapeutic target to reduce tumor proliferation and increase doxorubicin sensitivity through modulation of FOXM1, E2F1, and cell cycle/DNA repair proteins. Nature Publishing Group UK 2022-04-15 /pmc/articles/PMC9012789/ /pubmed/35428820 http://dx.doi.org/10.1038/s41598-022-10385-8 Text en © The Author(s) 2022 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/) .
spellingShingle Article
Hirschler-Laszkiewicz, Iwona
Festa, Fernanda
Huang, Suming
Moldovan, George-Lucian
Nicolae, Claudia
Dhoonmoon, Ashna
Bao, Lei
Keefer, Kerry
Chen, Shu-jen
Wang, Hong-Gang
Cheung, Joseph Y.
Miller, Barbara A.
The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1
title The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1
title_full The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1
title_fullStr The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1
title_full_unstemmed The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1
title_short The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1
title_sort human ion channel trpm2 modulates cell survival in neuroblastoma through e2f1 and foxm1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012789/
https://www.ncbi.nlm.nih.gov/pubmed/35428820
http://dx.doi.org/10.1038/s41598-022-10385-8
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