SGK1 signaling promotes glucose metabolism and survival in extracellular matrix detached cells
Open accessPublished version of a preprint
Abstract
Loss of integrin-mediated attachment to extracellular matrix (ECM) proteins can trigger a variety of cellular changes that affect cell viability. Foremost among these is the activation of anoikis, caspase-mediated cell death induced by ECM detachment. In addition, loss of ECM attachment causes profound alterations in cellular metabolism, which can lead to anoikis-independent cell death. Here, we describe a surprising role for serum and glucocorticoid kinase-1 (SGK1) in the promotion of energy production when cells are detached. Our data demonstrate that SGK1 activation is necessary and sufficient for ATP generation during ECM detachment and anchorage-independent growth. More specifically, SGK1 promotes a substantial elevation in glucose uptake because of elevated GLUT1 transcription. In addition, carbon flux into the pentose phosphate pathway (PPP) is necessary to accommodate elevated glucose uptake and PPP-mediated glyceraldehyde-3-phosphate (G3P) is necessary for ATP production. Thus, our data show SGK1 as master regulator of glucose metabolism and cell survival during ECM-detached conditions.
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The role of SGK1 in metabolic pathways and glucose uptake may be disrupted and potentially exacerbate the pathological process of Huntington's disease.
“The role of SGK1 in metabolic pathways and glucose uptake may be disrupted and potentially exacerbate the pathological process of HD”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Mason et al., 2021
Cites
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Induction of Autophagy during Extracellular Matrix Detachment Promotes Cell Survival
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Cancer cell survival during detachment from the ECM: multiple barriers to tumour progression
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Self-citationEMD638683, a Novel SGK Inhibitor with Antihypertensive Potency
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Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain
Howard, P. G., Zou, P., Zhang, Y., Huang, F., Tesic, V., Wu, C. Y.-C., & Lee, R. H.-C. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114973 · Cited by 13 · see citing works
- Authors
- Mason, J. A., Cockfield, J. A., Pape, D. J., Meissner, H., Sokolowski, M. T., White, T. C., Valentín López, J. C., Liu, J., Liu, X., Martínez-Reyes, I., Chandel, N. S., Locasale, J. W., & Schafer, Z. T.
- Affiliations
- University of Notre Dame (US)
- Duke University (US)
- Northwestern University (US)
- Corresponding author
- Schafer, Zachary T.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 34
- Issue
- 11
- Pages
- 108821
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W3138749955
- Cited by
- 64
- References
- 8
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 23 · 2023: 13 · 2022: 9 · 2021: 5
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Science Foundation
- American Cancer Society
- Coleman Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- SGK1, extracellular matrix detachment, anoikis, glucose metabolism, glucose uptake, pentose phosphate pathway, glyceraldehyde-3-phosphate, ATP production, anchorage-independent growth, cell survival
- MeSH terms
- Serum-Glucocorticoid Regulated Kinases, Adenosine Triphosphate, Animals, Cell Adhesion, Cell Line, Cell Survival, Extracellular Matrix, Glucose, Glyceraldehyde 3-Phosphate, Humans, Mitochondria, Oxidative Phosphorylation, Pentose Phosphate Pathway, Signal Transduction, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Cell Proliferation, Proto-Oncogene Proteins c-akt, Glucose Transporter Type 1, Mice
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