MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells.
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.
Godlewski
Jakub
J
Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA.
Nowicki
Michal O
MO
Bronisz
Agnieszka
A
Nuovo
Gerard
G
Palatini
Jeff
J
De Lay
Michael
M
Van Brocklyn
James
J
Ostrowski
Michael C
MC
Chiocca
E Antonio
EA
Lawler
Sean E
SE
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000222:Adaptation, Physiological; D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D019556:COS Cells; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D005947:Glucose / Q000172:deficiency; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics; D013997:Time Factors; D014162:Transfection
C540569:CAB39 protein, human; D002135:Calcium-Binding Proteins; C531201:MIRN451 microRNA, human; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose