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MCL1 nuclear translocation induces chemoresistance in colorectal carcinoma
Colorectal cancer (CRC) is one of the most common and deadliest forms of cancer. Myeloid Cell Leukemia 1 (MCL1), a pro-survival member of the Bcl-2 protein family is associated with chemo-resistance in CRC. The ability of MCL1 to inhibit apoptosis by binding to the BH3 domains of pro-apoptotic Bcl-2...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766550/ https://www.ncbi.nlm.nih.gov/pubmed/35042842 http://dx.doi.org/10.1038/s41419-021-04334-y |
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author | Fu, Dechen Pfannenstiel, Luke Demelash, Abeba Phoon, Yee Peng Mayell, Cameron Cabrera, Claudia Liu, Caini Zhao, Junjie Dermawan, Josephine Patil, Deepa DeVecchio, Jennifer Kalady, Matthew Souers, Andrew J. Phillips, Darren C. Li, Xiaoxia Gastman, Brian |
author_facet | Fu, Dechen Pfannenstiel, Luke Demelash, Abeba Phoon, Yee Peng Mayell, Cameron Cabrera, Claudia Liu, Caini Zhao, Junjie Dermawan, Josephine Patil, Deepa DeVecchio, Jennifer Kalady, Matthew Souers, Andrew J. Phillips, Darren C. Li, Xiaoxia Gastman, Brian |
author_sort | Fu, Dechen |
collection | PubMed |
description | Colorectal cancer (CRC) is one of the most common and deadliest forms of cancer. Myeloid Cell Leukemia 1 (MCL1), a pro-survival member of the Bcl-2 protein family is associated with chemo-resistance in CRC. The ability of MCL1 to inhibit apoptosis by binding to the BH3 domains of pro-apoptotic Bcl-2 family members is a well-studied means by which this protein confers resistance to multiple anti-cancer therapies. We found that specific DNA damaging chemotherapies promote nuclear MCL1 translocation in CRC models. In p53(null) CRC, this process is associated with resistance to chemotherapeutic agents, the mechanism of which is distinct from the classical mitochondrial protection. We previously reported that MCL1 has a noncanonical chemoresistance capability, which requires a novel loop domain that is distinct from the BH3-binding domain associated with anti-apoptotic function. Herein we disclose that upon treatment with specific DNA-damaging chemotherapy, this loop domain binds directly to alpha-enolase which in turn binds to calmodulin; we further show these protein−protein interactions are critical in MCL1’s nuclear import and chemoresistance. We additionally observed that in chemotherapy-treated p53(−/−) CRC models, MCL1 nuclear translocation confers sensitivity to Bcl-xL inhibitors, which has significant translational relevance given the co-expression of these proteins in CRC patient samples. Together these findings indicate that chemotherapy-induced MCL1 translocation represents a novel resistance mechanism in CRC, while also exposing an inherent and targetable Bcl-xL co-dependency in these cancers. The combination of chemotherapy and Bcl-xL inhibitors may thus represent a rational means of treating p53(−/−) CRC via exploitation of this unique MCL1-based chemoresistance mechanism. |
format | Online Article Text |
id | pubmed-8766550 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87665502022-02-04 MCL1 nuclear translocation induces chemoresistance in colorectal carcinoma Fu, Dechen Pfannenstiel, Luke Demelash, Abeba Phoon, Yee Peng Mayell, Cameron Cabrera, Claudia Liu, Caini Zhao, Junjie Dermawan, Josephine Patil, Deepa DeVecchio, Jennifer Kalady, Matthew Souers, Andrew J. Phillips, Darren C. Li, Xiaoxia Gastman, Brian Cell Death Dis Article Colorectal cancer (CRC) is one of the most common and deadliest forms of cancer. Myeloid Cell Leukemia 1 (MCL1), a pro-survival member of the Bcl-2 protein family is associated with chemo-resistance in CRC. The ability of MCL1 to inhibit apoptosis by binding to the BH3 domains of pro-apoptotic Bcl-2 family members is a well-studied means by which this protein confers resistance to multiple anti-cancer therapies. We found that specific DNA damaging chemotherapies promote nuclear MCL1 translocation in CRC models. In p53(null) CRC, this process is associated with resistance to chemotherapeutic agents, the mechanism of which is distinct from the classical mitochondrial protection. We previously reported that MCL1 has a noncanonical chemoresistance capability, which requires a novel loop domain that is distinct from the BH3-binding domain associated with anti-apoptotic function. Herein we disclose that upon treatment with specific DNA-damaging chemotherapy, this loop domain binds directly to alpha-enolase which in turn binds to calmodulin; we further show these protein−protein interactions are critical in MCL1’s nuclear import and chemoresistance. We additionally observed that in chemotherapy-treated p53(−/−) CRC models, MCL1 nuclear translocation confers sensitivity to Bcl-xL inhibitors, which has significant translational relevance given the co-expression of these proteins in CRC patient samples. Together these findings indicate that chemotherapy-induced MCL1 translocation represents a novel resistance mechanism in CRC, while also exposing an inherent and targetable Bcl-xL co-dependency in these cancers. The combination of chemotherapy and Bcl-xL inhibitors may thus represent a rational means of treating p53(−/−) CRC via exploitation of this unique MCL1-based chemoresistance mechanism. Nature Publishing Group UK 2022-01-18 /pmc/articles/PMC8766550/ /pubmed/35042842 http://dx.doi.org/10.1038/s41419-021-04334-y 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Fu, Dechen Pfannenstiel, Luke Demelash, Abeba Phoon, Yee Peng Mayell, Cameron Cabrera, Claudia Liu, Caini Zhao, Junjie Dermawan, Josephine Patil, Deepa DeVecchio, Jennifer Kalady, Matthew Souers, Andrew J. Phillips, Darren C. Li, Xiaoxia Gastman, Brian MCL1 nuclear translocation induces chemoresistance in colorectal carcinoma |
title | MCL1 nuclear translocation induces chemoresistance in colorectal carcinoma |
title_full | MCL1 nuclear translocation induces chemoresistance in colorectal carcinoma |
title_fullStr | MCL1 nuclear translocation induces chemoresistance in colorectal carcinoma |
title_full_unstemmed | MCL1 nuclear translocation induces chemoresistance in colorectal carcinoma |
title_short | MCL1 nuclear translocation induces chemoresistance in colorectal carcinoma |
title_sort | mcl1 nuclear translocation induces chemoresistance in colorectal carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766550/ https://www.ncbi.nlm.nih.gov/pubmed/35042842 http://dx.doi.org/10.1038/s41419-021-04334-y |
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