title: Rapamycin reverses NPM-ALK-induced glucocorticoid resistance in lymphoid tumor cells by inhibiting mTOR signaling pathway, enhancing G1 cell cycle arrest and apoptosis.
abstract: The anaplastic lymphoma kinase (ALK) is an oncogene product involved in hematopoietic and non-hematopoietic malignancies. Recent studies have demonstrated that nucleophosmin (NPM)-ALK, originated from the fusion of NPM and ALK genes, causes cell transformation through diverse mechanisms. Here, we show a novel mechanism by which NPM-ALK transforms lymphoid tumor cells to become resistant to glucocorticoid (GC) or dexamethasone (Dex) treatment. Transformed BaF3 cells by NPM-ALK were much more resistant to Dex compared with their parental cells, and concurrently had a constitutive activation of mammalian target of rapamycin (mTOR) signaling, as evidenced by hyperphosphorylation of its downstream effectors, p70 S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The mTOR inhibitor rapamycin suppressed activation of p70S6K in BaF3/NPM-ALK cells and reversed GC resistance by synergistically inhibiting mTOR signaling pathway, enhancing cell cycle arrest at G(1) phase and promoting apoptotic cell death. In conclusion, our data indicate that the ALK fusion kinase, NPM-ALK, induces GC resistance by activating mTOR signaling, and addition of mTOR inhibitors to the chemotherapeutic regimen of ALK+ lymphomas may improve the prognosis.
authors.affiliation: Laboratory of Hematology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: L
authors.initials: L
authors.lastname: Gu
authors.forename: J
authors.initials: J
authors.lastname: Gao
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: Y P
authors.initials: YP
authors.lastname: Zhu
authors.forename: C S
authors.initials: CS
authors.lastname: Jia
authors.forename: R Y
authors.initials: RY
authors.lastname: Fu
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: Q K
authors.initials: QK
authors.lastname: Liao
authors.forename: Z
authors.initials: Z
authors.lastname: Ma
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D039642:Eukaryotic Initiation Factors; D016193:G1 Phase / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D010750:Phosphoproteins; D003907:Dexamethasone; D011494:Protein Kinases; C107023:p80(NPM-ALK) protein; C546843:mTOR protein, mouse; D011505:Protein-Tyrosine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus