Cbl-b promotes chemotherapy-induced apoptosis in rat basophilic leukemia cells by suppressing PI3K/Akt activation and enhancing MEK/ERK activation

• DOI: 10.1007/s11010-010-0407-8
• Publication Date: 2010-02-22T23:41:07Z
• Authors: Xiujuan Qu; Yingchun Li; Jing Liu; Ling Xu; Ye Zhang; Xuejun Hu; Kezuo Hou; Yunpeng Liu
• Keywords: Mitogen-Activated Protein Kinase Kinases; 0301 basic medicine; Antimetabolites, Antineoplastic; Dose-Response Relationship, Drug; Cell Survival; Cytarabine; Apoptosis; Antineoplastic Agents, Phytogenic; 3. Good health; Enzyme Activation; Inhibitory Concentration 50; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Leukemia, Basophilic, Acute; Cell Line, Tumor; Mutation; Animals; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Proto-Oncogene Proteins c-akt; Adaptor Proteins, Signal Transducing; Etoposide; Phosphoinositide-3 Kinase Inhibitors

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.