Regulatory effects of a Mnk2-eIF4E feedback loop during mTORC1 targeting of human medulloblastoma cells
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Frank Eckerdt1, Elspeth Beauchamp1,2, Jonathan Bell1, Asneha Iqbal1,3, Bing Su4,5 , Rikiro Fukunaga6, Rishi R. Lulla1,3, Stewart Goldman1,3 and Leonidas C. Platanias1,2
1 Robert H. Lurie Comprehensive Cancer Center and Division of Hematology- Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL,USA
2 Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA
3 Division of Hematology and Oncology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
4 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
5 Shanghai Institute of Immunology Department of Microbiology and Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China
6 Laboratory of Biochemistry, Osaka University of Pharmaceutical Sciences, Osaka, Japan
Leonidas C. Platanias, email:
Keywords: TOR, Mnk, rapamycin, medulloblastoma
Received: June 26, 2014 Accepted: August 05, 2014 Published: August 06, 2014
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.
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