mTOR inhibitor RAD001 (Everolimus) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c-ABL protein

Manuela Mancini; Valentina Corradi; Sara Petta; Giovanni Martinelli; Enza Barbieri; Maria Alessandra Santucci

doi:10.1016/j.leukres.2009.07.012

mTOR inhibitor RAD001 (Everolimus) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c-ABL protein

Leuk Res. 2010 May;34(5):641-8. doi: 10.1016/j.leukres.2009.07.012. Epub 2009 Jul 29.

Authors

Manuela Mancini¹, Valentina Corradi, Sara Petta, Giovanni Martinelli, Enza Barbieri, Maria Alessandra Santucci

Affiliation

¹ Dipartimento di Ematologia e Scienze Oncologiche Lorenzo e Ariosto Seràgnoli, University of Bologna, Italy. mancini_manu@yahoo.com

PMID: 19643477
DOI: 10.1016/j.leukres.2009.07.012

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Benzamides
Blotting, Western
Cell Line, Tumor
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Cell Separation
Everolimus
Flow Cytometry
Gene Expression / drug effects*
Humans
Imatinib Mesylate
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
Microscopy, Confocal
Piperazines / administration & dosage
Protein Processing, Post-Translational / drug effects
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Transport / drug effects
Proto-Oncogene Proteins c-abl / biosynthesis
Proto-Oncogene Proteins c-abl / drug effects*
Pyrimidines / administration & dosage
Sirolimus / administration & dosage
Sirolimus / analogs & derivatives
TOR Serine-Threonine Kinases

Substances

Benzamides
Intracellular Signaling Peptides and Proteins
Piperazines
Pyrimidines
Imatinib Mesylate
Everolimus
MTOR protein, human
Proto-Oncogene Proteins c-abl
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases
Sirolimus