microRNA-451: A conditional switch controlling glioma cell proliferation and migration.
Glioblastoma, the most common and aggressive primary brain tumor, is rapidly growing and highly infiltrative. Incomplete knowledge of the molecular biology, genetics, causes and cellular origin of these tumors may limit the development of improved therapeutics. A major and fundamental advance in recent years has been the identification of microRNAs as highly conserved regulators of gene expression. Here we will discuss further our recently published data on the role of miR-451 in the biology of glioblastoma. We initially identified miR-451 due to its downregulation in a glioma cell migration assay. We then found that by targeting the LKB1 kinase complex miR-451 suppresses the activity of downstream protein kinases including the major energy biosensor AMPK. MiR-451 levels are regulated by glucose; under conditions of abundant energy miR-451 expression is high, and the suppression of AMPK signaling allows cells to maintain elevated proliferation rates via unrestrained mTOR activation. Under conditions of glucose withdrawal, miR-451 downregulation is necessary for AMPK pathway activation, leading to suppressed proliferation rates, increased cell survival and migration. We also identified a potential feedback loop between LKB1 and miR-451, which allows a sustained and robust response to glucose deprivation. This data will be discussed in the context of potential biological significance and therapeutic implications.
Godlewski
Jakub
J
Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.
Bronisz
Agnieszka
A
Nowicki
Michal O
MO
Chiocca
E Antonio
EA
Lawler
Sean
S
D000091162:AMP-Activated Protein Kinase Kinases; D000951:Antigens, Neoplasm / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D005909:Glioblastoma / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
D000951:Antigens, Neoplasm; D051017:Apoptosis Regulatory Proteins; C534238:CAB39L protein, human; C531201:MIRN451 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D005947:Glucose