title: Cbl-b promotes chemotherapy-induced apoptosis in rat basophilic leukemia cells by suppressing PI3K/Akt activation and enhancing MEK/ERK activation.
abstract: The ubiquitin ligase Cbl-b is a negative regulator of the PI3K/Akt pathway, the survival pathway implicated in chemotherapy resistance. However, it remains unclear whether Cbl-b can regulate chemosensitivity through modulating Akt activation. In this study, VP-16-induced RBL-2H3 cells apoptosis was accompanied by the activation of Akt and ERK. The PI3K inhibitor LY294002, not the ERK inhibitor PD98059, enhanced the apoptosis. In addition, down-regulation of Cbl-b was also detected. Over expression of Cbl-b significantly enhanced VP-16-induced cell apoptosis with inhibition of Akt activity, while a dominant negative (DN) RING Finger domain mutation completely abolished this enhancement. On the other hand, ERK activity was enhanced by Cbl-b, and the ERK inhibitor PD98059 reversed Cbl-b-enhanced apoptosis. The consistent results were also showed in the process of Ara-c treatment. These observations indicate that Cbl-b promotes RBL-2H3 apoptosis induced by VP-16 or Ara-c, probably through inhibition of Akt and activation of ERK.
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, No. 155, North Nanjing Street, Heping District, 110001 Shenyang, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Qu
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xuejun
authors.initials: X
authors.lastname: Hu
authors.forename: Kezuo
authors.initials: K
authors.lastname: Hou
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003561:Cytarabine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D015471:Leukemia, Basophilic, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013997:Time Factors; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D003561:Cytarabine; D004791:Enzyme Inhibitors; D005047:Etoposide; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D050721:Proto-Oncogene Proteins c-cbl; C492213:Cblb protein, rat