NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress
Abstract Cancers, including glioblastoma multiforme (GBM), undergo coordinated reprogramming of metabolic pathways that control glycolysis and oxidative phosphorylation (OXPHOS) to promote tumor growth in diverse tumor microenvironments. Adaptation to limited nutrient availability in the microenviro...
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doaj-2f0bf402e3484a34827201f03d1b909a2021-03-21T12:05:46ZengNature Publishing GroupCell Death and Disease2041-48892021-03-0112311810.1038/s41419-020-03383-zNIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stressMichael L. Kamradt0Ji-Ung Jung1Kathryn M. Pflug2Dong W. Lee3Victor Fanniel4Raquel Sitcheran5Department of Molecular & Cellular Medicine, Texas A&M University Health Science CenterDepartment of Molecular & Cellular Medicine, Texas A&M University Health Science CenterDepartment of Molecular & Cellular Medicine, Texas A&M University Health Science CenterDepartment of Molecular & Cellular Medicine, Texas A&M University Health Science CenterDepartment of Molecular & Cellular Medicine, Texas A&M University Health Science CenterDepartment of Molecular & Cellular Medicine, Texas A&M University Health Science CenterAbstract Cancers, including glioblastoma multiforme (GBM), undergo coordinated reprogramming of metabolic pathways that control glycolysis and oxidative phosphorylation (OXPHOS) to promote tumor growth in diverse tumor microenvironments. Adaptation to limited nutrient availability in the microenvironment is associated with remodeling of mitochondrial morphology and bioenergetic capacity. We recently demonstrated that NF-κB-inducing kinase (NIK) regulates mitochondrial morphology to promote GBM cell invasion. Here, we show that NIK is recruited to the outer membrane of dividing mitochondria with the master fission regulator, Dynamin-related protein1 (DRP1). Moreover, glucose deprivation-mediated metabolic shift to OXPHOS increases fission and mitochondrial localization of both NIK and DRP1. NIK deficiency results in decreased mitochondrial respiration, ATP production, and spare respiratory capacity (SRC), a critical measure of mitochondrial fitness. Although IκB kinase α and β (IKKα/β) and NIK are required for OXPHOS in high glucose media, only NIK is required to increase SRC under glucose deprivation. Consistent with an IKK-independent role for NIK in regulating metabolism, we show that NIK phosphorylates DRP1-S616 in vitro and in vivo. Notably, a constitutively active DRP1-S616E mutant rescues oxidative metabolism, invasiveness, and tumorigenic potential in NIK−/− cells without inducing IKK. Thus, we establish that NIK is critical for bioenergetic stress responses to promote GBM cell pathogenesis independently of IKK. Our data suggest that targeting NIK may be used to exploit metabolic vulnerabilities and improve therapeutic strategies for GBM.https://doi.org/10.1038/s41419-020-03383-z |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michael L. Kamradt Ji-Ung Jung Kathryn M. Pflug Dong W. Lee Victor Fanniel Raquel Sitcheran |
spellingShingle |
Michael L. Kamradt Ji-Ung Jung Kathryn M. Pflug Dong W. Lee Victor Fanniel Raquel Sitcheran NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress Cell Death and Disease |
author_facet |
Michael L. Kamradt Ji-Ung Jung Kathryn M. Pflug Dong W. Lee Victor Fanniel Raquel Sitcheran |
author_sort |
Michael L. Kamradt |
title |
NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress |
title_short |
NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress |
title_full |
NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress |
title_fullStr |
NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress |
title_full_unstemmed |
NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress |
title_sort |
nik promotes metabolic adaptation of glioblastoma cells to bioenergetic stress |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-03-01 |
description |
Abstract Cancers, including glioblastoma multiforme (GBM), undergo coordinated reprogramming of metabolic pathways that control glycolysis and oxidative phosphorylation (OXPHOS) to promote tumor growth in diverse tumor microenvironments. Adaptation to limited nutrient availability in the microenvironment is associated with remodeling of mitochondrial morphology and bioenergetic capacity. We recently demonstrated that NF-κB-inducing kinase (NIK) regulates mitochondrial morphology to promote GBM cell invasion. Here, we show that NIK is recruited to the outer membrane of dividing mitochondria with the master fission regulator, Dynamin-related protein1 (DRP1). Moreover, glucose deprivation-mediated metabolic shift to OXPHOS increases fission and mitochondrial localization of both NIK and DRP1. NIK deficiency results in decreased mitochondrial respiration, ATP production, and spare respiratory capacity (SRC), a critical measure of mitochondrial fitness. Although IκB kinase α and β (IKKα/β) and NIK are required for OXPHOS in high glucose media, only NIK is required to increase SRC under glucose deprivation. Consistent with an IKK-independent role for NIK in regulating metabolism, we show that NIK phosphorylates DRP1-S616 in vitro and in vivo. Notably, a constitutively active DRP1-S616E mutant rescues oxidative metabolism, invasiveness, and tumorigenic potential in NIK−/− cells without inducing IKK. Thus, we establish that NIK is critical for bioenergetic stress responses to promote GBM cell pathogenesis independently of IKK. Our data suggest that targeting NIK may be used to exploit metabolic vulnerabilities and improve therapeutic strategies for GBM. |
url |
https://doi.org/10.1038/s41419-020-03383-z |
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