Abstract
To sustain tumor growth, cancer cells must be able to adapt to fluctuations in energy availability. We have identified a single microRNA that controls glioma cell proliferation, migration, and responsiveness to glucose deprivation. Abundant glucose allows relatively high miR-451 expression, promoting cell growth. In low glucose, miR-451 levels decrease, slowing proliferation but enhancing migration and survival. This allows cells to survive metabolic stress and seek out favorable growth conditions. In glioblastoma patients, elevated miR-451 is associated with shorter survival. The effects of miR-451 are mediated by LKB1, which it represses through targeting its binding partner, CAB39 (MO25 alpha). Overexpression of miR-451 sensitized cells to glucose deprivation, suggesting that its downregulation is necessary for robust activation of LKB1 in response to metabolic stress. Thus, miR-451 is a regulator of the LKB1/AMPK pathway, and this may represent a fundamental mechanism that contributes to cellular adaptation in response to altered energy availability.
(c) 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism*
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Adaptation, Physiological
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Animals
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Brain Neoplasms / enzymology*
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Brain Neoplasms / genetics
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Brain Neoplasms / mortality
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Brain Neoplasms / pathology
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COS Cells
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Calcium-Binding Proteins / metabolism
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Cell Movement
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Cell Proliferation
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Cell Survival
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Chlorocebus aethiops
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Enzyme Activation
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Glioblastoma / enzymology*
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Glioblastoma / genetics
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Glioblastoma / mortality
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Glioblastoma / pathology
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Glucose / deficiency
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HeLa Cells
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Humans
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MicroRNAs / metabolism*
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Prognosis
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction* / genetics
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Stress, Physiological* / genetics
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Time Factors
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Transfection
Substances
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CAB39 protein, human
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Calcium-Binding Proteins
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MIRN451 microRNA, human
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MicroRNAs
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Protein Serine-Threonine Kinases
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STK11 protein, human
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases
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Glucose