title: Regulatory effects of a Mnk2-eIF4E feedback loop during mTORC1 targeting of human medulloblastoma cells.
abstract: The mTOR pathway controls mRNA translation of mitogenic proteins and is a central regulator of metabolism in malignant cells. Development of malignant cell resistance is a limiting factor to the effects of mTOR inhibitors, but the mechanisms accounting for such resistance are not well understood. We provide evidence that mTORC1 inhibition by rapamycin results in engagement of a negative feedback regulatory loop in malignant medulloblastoma cells, involving phosphorylation of the eukaryotic translation-initiation factor eIF4E. This eIF4E phosphorylation is Mnk2- mediated, but Mnk1-independent, and acts as a survival mechanism for medulloblastoma cells. Pharmacological targeting of Mnk1/2 or siRNA-mediated knockdown of Mnk2 sensitizes medulloblastoma cells to mTOR inhibition and promotes suppression of malignant cell proliferation and anchorage-independent growth. Altogether, these findings provide evidence for the existence of a Mnk2-controlled feedback loop in medulloblastoma cells that accounts for resistance to mTOR inhibitors, and raise the potential for combination treatments of mTOR and Mnk inhibitors for the treatment of medulloblastoma.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Eckerdt
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.
authors.forename: Elspeth
authors.initials: E
authors.lastname: Beauchamp
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bell
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Division of Hematology and Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
authors.forename: Asneha
authors.initials: A
authors.lastname: Iqbal
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Shanghai Institute of Immunology Department of Microbiology and Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Su
authors.affiliation: Laboratory of Biochemistry, Osaka University of Pharmaceutical Sciences, Osaka, Japan.
authors.forename: Rikiro
authors.initials: R
authors.lastname: Fukunaga
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Division of Hematology and Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
authors.forename: Rishi R
authors.initials: RR
authors.lastname: Lulla
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Division of Hematology and Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA; Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008527:Medulloblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection
chemical_list: D000903:Antibiotics, Antineoplastic; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; C486342:MKNK2 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus