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: Xiujuan Qu, Yingchun Li, Jing Liu, Ling Xu, Ye Zhang, Xuejun Hu, Kezuo Hou, Yunpeng Liu
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 340 Issue 1-2 Pg. 107-14 (Jul 2010) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 20177738 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antimetabolites, Antineoplastic
• Antineoplastic Agents, Phytogenic
• Cblb protein, rat
• Enzyme Inhibitors
• Phosphoinositide-3 Kinase Inhibitors
• Cytarabine
• Etoposide
• Proto-Oncogene Proteins c-cbl
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase Kinases

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival
• Cytarabine (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Etoposide (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Inhibitory Concentration 50
• Leukemia, Basophilic, Acute (enzymology, genetics, pathology)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Mutation
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-cbl (genetics, metabolism)
• Rats
• Time Factors
• Transfection