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

被引：28
|
作者：
Mancini, Manuela [1 ]
Corradi, Valentina [2 ]
Petta, Sara [1 ]
Martinelli, Giovanni [1 ]
Barbieri, Enza [3 ]
Santucci, Maria Alessandra [1 ]
机构：
[1] Univ Bologna, Dipartimento Ematol & Sci Oncol Lorenzo & Ariosto, I-40126 Bologna, Italy
[2] Univ Siena, Dipartimento Farmaco Chim Tecnol, I-53100 Siena, Italy
[3] Univ Bologna, Ist Radioterapia Luigi Galvani, I-40126 Bologna, Italy
来源：
LEUKEMIA RESEARCH | 2010年 / 34卷 / 05期
关键词：
Chronic myeloid leukemia; p210; BCR-ABL; p145; c-ABL; Imatinib mesylate; mTOR; RAD001; MAMMALIAN TARGET; TYROSINE KINASE; DNA-DAMAGE; RAPAMYCIN MTOR; BCR; PHOSPHORYLATION; ACTIVATION; CELLS; PATHWAY; TRANSLATION;
D O I：
10.1016/j.leukres.2009.07.012
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
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. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码：641 / 648
页数：8
相关论文
共 12 条
  • [1] RAD 001 (Everolimus) Prevents mTOR and Akt Late Re-Activation in Response to Imatinib in Chronic Myeloid Leukemia
    Mancini, Manuela
    Petta, Sara
    Martinelli, Giovanni
    Barbieri, Enza
    Santucci, Maria A.
    JOURNAL OF CELLULAR BIOCHEMISTRY, 2010, 109 (02) : 320 - 328
  • [2] Effects of mTOR Inhibitor Everolimus (RAD001) on Bladder Cancer Cells
    Chiong, Edmund
    Lee, I-Ling
    Dadbin, Ali
    Sabichi, Anita L.
    Harris, Loleta
    Urbauer, Diana
    McConkey, David J.
    Dickstein, Rian J.
    Cheng, Tiewei
    Grossman, H. Barton
    CLINICAL CANCER RESEARCH, 2011, 17 (09) : 2863 - 2873
  • [3] 14-3-3 Ligand Prevents Nuclear Import of c-ABL Protein in Chronic Myeloid Leukemia
    Mancini, Manuela
    Veljkovic, Nevena
    Corradi, Valentina
    Zuffa, Elisa
    Corrado, Patrizia
    Pagnotta, Eleonora
    Martinelli, Giovanni
    Barbieri, Enza
    Santucci, Maria Alessandra
    TRAFFIC, 2009, 10 (06) : 637 - 647
  • [4] The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells
    Kuwatsuka, Y.
    Minami, M.
    Minami, Y.
    Sugimoto, K.
    Hayakawa, F.
    Miyata, Y.
    Abe, A.
    Goff, D. J.
    Kiyoi, H.
    Naoe, T.
    BLOOD CANCER JOURNAL, 2011, 1 : e17 - e17
  • [5] The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells
    Zitzmann, Kathrin
    De Toni, Enrico N.
    Brand, Stephan
    Goeke, Burkhard
    Meinecke, Jennifer
    Spoettl, Gerald
    Meyer, Heinrich H. D.
    Auernhammer, Christoph J.
    NEUROENDOCRINOLOGY, 2007, 85 (01) : 54 - 60
  • [6] C-Abl Inhibitor Imatinib Enhances Insulin Production by β Cells: C-Abl Negatively Regulates Insulin Production via Interfering with the Expression of NKx2.2 and GLUT-2
    Xia, Chang-Qing
    Zhang, Pengcheng
    Li, Shiwu
    Yuan, Lihui
    Xia, Tina
    Xie, Chao
    Clare-Salzler, Michael J.
    PLOS ONE, 2014, 9 (05):
  • [7] Identification of the first non-peptidic small molecule inhibitor of the c-Abl/14-3-3 protein-protein interactions able to drive sensitive and Imatinib-resistant leukemia cells to apoptosis
    Corradi, Valentina
    Mancini, Manuela
    Manetti, Fabrizio
    Petta, Sara
    Santucci, Maria Alessandra
    Botta, Maurizio
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (20) : 6133 - 6137
  • [8] Propofol enhances BCR-ABL TKIs' inhibitory effects in chronic myeloid leukemia through Akt/mTOR suppression
    Tan, Zhimin
    Peng, Aixia
    Xu, Jingwen
    Ouyang, Mingwen
    BMC ANESTHESIOLOGY, 2017, 17
  • [9] Proteasome inhibitor MG-132 enhances histone deacetylase inhibitor SAHA-induced cell death of chronic myeloid leukemia cells by an ROS-mediated mechanism and downregulation of the Bcr-Abl fusion protein
    Zhou, Wenjing
    Zhu, Weiwei
    Ma, Liya
    Xiao, Feng
    Qian, Wenbin
    Oncology Letters, 2015, 10 (05) : 2899 - 2904
  • [10] A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy
    Borthakur, Gautam
    Dombret, Herve
    Schafhausen, Philippe
    Brummendorf, Tim Henrik
    Boissel, Nicolas
    Jabbour, Elias
    Mariani, Mariangela
    Capolongo, Laura
    Carpinelli, Patrizia
    Davite, Cristina
    Kantarjian, Hagop
    Cortes, Jorge E.
    HAEMATOLOGICA, 2015, 100 (07) : 898 - 904
12