Intracellular C4BPA Levels Regulate NF-κB-Dependent Apoptosis
Summary: The importance of innate immunity in cancer is increasingly being recognized with recent reports suggesting tumor cell-intrinsic intracellular functions for innate immunity proteins. However, such functions are often poorly understood, and it is unclear whether these are affected by patient...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-10-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220307860 |
| _version_ | 1828894818417246208 |
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| author | Monica M. Olcina Ryan K. Kim Nikolas G. Balanis Caiyun Grace Li Rie von Eyben Thomas G. Graeber Daniel Ricklin Manuel Stucki Amato J. Giaccia |
| author_facet | Monica M. Olcina Ryan K. Kim Nikolas G. Balanis Caiyun Grace Li Rie von Eyben Thomas G. Graeber Daniel Ricklin Manuel Stucki Amato J. Giaccia |
| author_sort | Monica M. Olcina |
| collection | DOAJ |
| description | Summary: The importance of innate immunity in cancer is increasingly being recognized with recent reports suggesting tumor cell-intrinsic intracellular functions for innate immunity proteins. However, such functions are often poorly understood, and it is unclear whether these are affected by patient-specific mutations. Here, we show that C4b-binding protein alpha chain (C4BPA), typically thought to reside in the extracellular space, is expressed intracellularly in cancer cells, where it interacts with the NF-κB family member RelA and regulates apoptosis. Interestingly, intracellular C4BPA expression is regulated in a stress- and mutation-dependent manner and C4BPA mutations are associated with improved cancer survival outcome. Using cell lines harboring patient-specific C4BPA mutations, we show that increasing intracellular C4BPA levels correlate with sensitivity to oxaliplatin-induced apoptosis in vitro and in vivo. Mechanistically, sensitive C4BPA mutants display increased IκBα expression and increased inhibitory IκBα-RelA complex stability. These data suggest a non-canonical intracellular role for C4BPA in regulating NF-κB-dependent apoptosis. |
| first_indexed | 2024-12-13T14:18:18Z |
| format | Article |
| id | doaj.art-64c2b7db01984770a3fda8aeaa8c2c2f |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-13T14:18:18Z |
| publishDate | 2020-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-64c2b7db01984770a3fda8aeaa8c2c2f2022-12-21T23:42:11ZengElsevieriScience2589-00422020-10-012310101594Intracellular C4BPA Levels Regulate NF-κB-Dependent ApoptosisMonica M. Olcina0Ryan K. Kim1Nikolas G. Balanis2Caiyun Grace Li3Rie von Eyben4Thomas G. Graeber5Daniel Ricklin6Manuel Stucki7Amato J. Giaccia8Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA; Department of Gynecology, University of Zurich, Wagistrasse 14, 8952 Schlieren, Switzerland; Corresponding authorDepartment of Radiation Oncology, Stanford University, Stanford, CA 94305, USADepartment of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USADepartment of Radiation Oncology, Stanford University, Stanford, CA 94305, USADepartment of Radiation Oncology, Stanford University, Stanford, CA 94305, USADepartment of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USADepartment of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, SwitzerlandDepartment of Gynecology, University of Zurich, Wagistrasse 14, 8952 Schlieren, SwitzerlandDepartment of Radiation Oncology, Stanford University, Stanford, CA 94305, USA; Oxford Institute of Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX37DQ, UKSummary: The importance of innate immunity in cancer is increasingly being recognized with recent reports suggesting tumor cell-intrinsic intracellular functions for innate immunity proteins. However, such functions are often poorly understood, and it is unclear whether these are affected by patient-specific mutations. Here, we show that C4b-binding protein alpha chain (C4BPA), typically thought to reside in the extracellular space, is expressed intracellularly in cancer cells, where it interacts with the NF-κB family member RelA and regulates apoptosis. Interestingly, intracellular C4BPA expression is regulated in a stress- and mutation-dependent manner and C4BPA mutations are associated with improved cancer survival outcome. Using cell lines harboring patient-specific C4BPA mutations, we show that increasing intracellular C4BPA levels correlate with sensitivity to oxaliplatin-induced apoptosis in vitro and in vivo. Mechanistically, sensitive C4BPA mutants display increased IκBα expression and increased inhibitory IκBα-RelA complex stability. These data suggest a non-canonical intracellular role for C4BPA in regulating NF-κB-dependent apoptosis.http://www.sciencedirect.com/science/article/pii/S2589004220307860GeneticsImmunologyCancer |
| spellingShingle | Monica M. Olcina Ryan K. Kim Nikolas G. Balanis Caiyun Grace Li Rie von Eyben Thomas G. Graeber Daniel Ricklin Manuel Stucki Amato J. Giaccia Intracellular C4BPA Levels Regulate NF-κB-Dependent Apoptosis iScience Genetics Immunology Cancer |
| title | Intracellular C4BPA Levels Regulate NF-κB-Dependent Apoptosis |
| title_full | Intracellular C4BPA Levels Regulate NF-κB-Dependent Apoptosis |
| title_fullStr | Intracellular C4BPA Levels Regulate NF-κB-Dependent Apoptosis |
| title_full_unstemmed | Intracellular C4BPA Levels Regulate NF-κB-Dependent Apoptosis |
| title_short | Intracellular C4BPA Levels Regulate NF-κB-Dependent Apoptosis |
| title_sort | intracellular c4bpa levels regulate nf κb dependent apoptosis |
| topic | Genetics Immunology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220307860 |
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