Inhibition of MNK pathways enhances cancer cell response to chemotherapy with temozolomide and targeted radionuclide therapy.
Current standard-of-care treatment for malignant cancers includes radiotherapy and adjuvant chemotherapy. Here, we report increased MAP kinase-interacting kinase (MNK)-regulated phosphorylation of translation initiation factor 4E (eIF4E) in glioma cells upon temozolomide (TMZ) treatment and in medullary thyroid carcinoma (MTC) cells in response to targeted radionuclide therapy. Depletion of MNK activity by using two MNK inhibitors, CGP57380 or cercosporamide, as well as by MNK1-specific knockdown sensitized glioblastoma (GBM) cells and GBM-derived spheres to TMZ. Furthermore, CGP57380 treatment enhanced response of MTC cells to (177)Lu-labeled gastrin analogue. In order to understand how MNK signaling pathways support glioma survival we analyzed putative MNK substrates by quantitative phosphoproteomics in normal condition and in the presence of TMZ. We identified MNK inhibitor-sensitive phosphorylation sites on eIF4G1, mutations of which either influenced eIF4E phosphorylation or glioma cell response to TMZ, pointing to altered regulation of translation initiation as a resistance mechanism. Pharmacological inhibition of overexpressed MNK1 by CGP57380 reduced eIF4E phosphorylation and induced association of inactive MNK1 with eIF4G1. Taken together, our data show an activation of MNK-mediated survival mechanisms in response to either glioma chemotherapy or MTC targeted radiation and suggest that inhibition of MNK activity represents an attractive sensitizing strategy for cancer treatments.
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland. Electronic address: michal.grzmil@psi.ch.
Michal
M
Grzmil
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Jan
J
Seebacher
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Daniel
D
Hess
Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland.
Martin
M
Behe
Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland; Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
Roger
R
Schibli
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Gerald
G
Moncayo
Division of Neuropathology, Institute of Pathology, University of Basel, Switzerland.
Stephan
S
Frank
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Brian A
BA
Hemmings
D000814:Aniline Compounds; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D005755:Gastrins / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008187:Lutetium; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040901:Proteomics; D011687:Purines; D011868:Radioisotopes / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide
D000814:Aniline Compounds; D000970:Antineoplastic Agents; C466997:CGP 57380; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D005755:Gastrins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D011868:Radioisotopes; D008187:Lutetium; D003606:Dacarbazine; C000615061:Lutetium-177; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases; D000077204:Temozolomide
Glioma; MNK; MTC; Temozolomide; eIF4E; eIF4G