mTOR inhibitor RAD001 (Everolimus) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c-ABL protein.
Constitutive tyrosine kinase (TK) activity of p210 BCR-ABL fusion protein of chronic myeloid leukemia (CML) usurps physiological functions of normal p145 c-ABL protein. Accordingly, its inhibition by imatinib mesylate (IM) lets p145 c-ABL translocate into the nuclear compartment, which drives cell growth arrest and apoptotic death. Here we show that IM and the mammalian target of rapamycin (mTOR) inhibitor RAD001 (Everolimus) have additive effects on BCR-ABL-expressing cells. Those effects are at least partly conditional upon the enhanced nuclear accumulation of p145 c-ABL through events encompassing post-translational modifications of p145 c-ABL (Thr(735) phosphorylation) precluding its nuclear export and of 14-3-3 sigma (Ser(186) phosphorylation by c-Jun N-terminal kinase [JNK]) promoting p145 c-ABL nuclear re-import.
Mancini
Manuela
M
Dipartimento di Ematologia e Scienze Oncologiche Lorenzo e Ariosto Seràgnoli, University of Bologna, Italy. mancini_manu@yahoo.com
Corradi
Valentina
V
Petta
Sara
S
Martinelli
Giovanni
G
Barbieri
Enza
E
Santucci
Maria Alessandra
MA
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002469:Cell Separation; D000068338:Everolimus; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D010879:Piperazines / Q000008:administration & dosage; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D021381:Protein Transport / Q000187:drug effects; D016315:Proto-Oncogene Proteins c-abl / Q000096:biosynthesis / Q000187:drug effects*; D011743:Pyrimidines / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases
D001549:Benzamides; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000068338:Everolimus; C546842:MTOR protein, human; D016315:Proto-Oncogene Proteins c-abl; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus