NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress |
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Authors: | Michael L. Kamradt Ji-Ung Jung Kathryn M. Pflug Dong W. Lee Victor Fanniel Raquel Sitcheran |
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Affiliation: | 1.Department of Molecular & Cellular Medicine, Texas A&M University Health Science Center, College Station, TX 77845 USA ;2.Medical Sciences Graduate Program, Texas A&M University Health Science Center, College Station, TX 77845 USA ;3.Interdisciplinary Graduate Program in Genetics, Texas A&M University, College Station, TX 77845 USA ;4.Present Address: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA |
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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.Subject terms: Cancer metabolism, Energy metabolism, Cancer metabolism |
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