Bim protein degradation contributes to Cisplatin resistance.
Summary of "Bim protein degradation contributes to Cisplatin resistance."
Cisplatin is the first-line chemotherapy for the treatment of several cancers. However, the development of cisplatin resistance represents a major clinical problem, and the mechanisms of acquired resistance are not fully understood. Here we show that degradation of the Bcl-2 homology 3-only proapoptotic protein Bim plays an important role in cisplatin resistance in ovarian cancer. Specifically, we show that treatment of ovarian cancer cells with cisplatin caused Bim phosphorylation and subsequent degradation and that its degradation is associated with cisplatin resistance. We also show that cisplatin treatment caused the activation of ERK, which correlated with Bim phosphorylation and degradation. By inhibiting ERK phosphorylation with the MEK inhibitor and knocking down ERK expression with siRNA, we show that Bim phosphorylation and degradation were blocked, which suggests that Bim is phosphorylated by ERK and that such phosphorylation is responsible for cisplatin-induced Bim degradation. We show that ERK was activated in cisplatin-resistant OV433 cells as compared with their counterpart parental OV433 cells. We also show that Bim was phosphorylated and degraded in cisplatin-resistant OV433 cells but not in the parental OV433 cells. Importantly, we show that inhibition of Bim degradation by the proteasome inhibitor MG132 sensitized resistant OV433 cells to cisplatin-induced death. Taken together, our data indicate that degradation of Bim via ERK-mediated phosphorylation can lead to cisplatin resistance. Therefore, these findings suggest that cisplatin resistance can be overcome by the combination of cisplatin and the proteasome inhibitors in ovarian cancer cells.
Affiliation
From the Program in Molecular Biology and Genetics, Karmanos Cancer Institute, Departments of Oncology and Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201.
Journal Details
This article was published in the following journal.
Name: The Journal of biological chemistry
ISSN: 1083-351X
Pages: 22384-92
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21561860
- DOI: http://dx.doi.org/10.1074/jbc.M111.239566
Medical and Biotech [MESH] Definitions
Cisplatin
An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle.
Activated Protein C Resistance
A hemostatic disorder characterized by a poor anticoagulant response to activated protein C (APC). The activated form of Factor V (Factor Va) is more slowly degraded by activated protein C. Factor V Leiden mutation (R506Q) is the most common cause of APC resistance.
Beta-lactam Resistance
Nonsusceptibility of bacteria to the action of the beta-lactam antibiotics. Mechanisms responsible for beta-lactam resistance may be degradation of antibiotics by BETA-LACTAMASES, failure of antibiotics to penetrate, or low-affinity binding of antibiotics to targets.
Glycosylation End Products, Advanced
Products derived from the nonenzymatic reaction of glucose and proteins in vivo that exhibit a yellow-brown pigmentation and an ability to participate in protein-protein cross-linking. These substances are involved in biological processes relating to protein turnover and it is believed that their excessive accumulation contributes to the chronic complications of diabetes mellitus.
Mafb Transcription Factor
A large maf protein that regulates HINDBRAIN development, contributes to CELL DIFFERENTIATION of MONOCYTES, and interacts with ETS-1 TRANSCRIPTION FACTOR.
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