Open AccessOverexpression of BMI‐1 correlates with drug resistance in B‐cell lymphoma cells through the stabilization of survivin expression
Author(s) -
Bhattacharyya Joyeeta,
Mihara Keichiro,
Ohtsubo Motoaki,
Yasunaga Shin’ichiro,
Takei Yoshifumi,
Yanagihara Kazuyoshi,
Sakai Akira,
Hoshi Masaharu,
Takihara Yoshihiro,
Kimura Akiro
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.02121.x
Subject(s) - survivin , etoposide , cancer research , medicine , lymphoma , downregulation and upregulation , drug resistance , gene knockdown , irinotecan , cancer , cell culture , chemotherapy , biology , gene , colorectal cancer , biochemistry , genetics , microbiology and biotechnology
The expression of BMI‐1 is correlated with disease progression in cancer patients. We showed that ectopic expression of BMI‐1 in B‐cell lymphoma cell lines, HT and RL, conferred resistance to etoposide and oxaliplatin, known to enhance sensitivity by targeting the survivin gene, but not to irinotecan, which is not relevant to the downregulation of survivin expression. The expression of survivin was not only augmented in cells transduced with BMI‐1, but persisted in the presence of etoposide in cells overexpressing BMI‐1. By contrast, the mock‐transduced cells succumbed in the medium with anticancer drugs, with an accompanying decrease in BMI‐1 and survivin expression. BMI‐1 overexpression stabilized survivin post‐translationally without an accompanying rise in the mRNA, suggesting survivin as a potential target for BMI‐1. Knockdown of either BMI‐1 or survivin restored sensitivity to etoposide in the BMI‐1‐overexpressing lymphoma cells. An analysis of six patients with B‐cell lymphoma showed that in the drug‐resistant patients, levels of BMI‐1 and survivin were maintained even after drug administration. However, downregulation of both BMI‐1 and survivin expression was observed in the drug‐sensitive patients. Therefore, BMI‐1 might facilitate drug resistance in B‐cell lymphoma cells through the regulation of survivin. BMI‐1 could be an important prognostic marker as well as a future therapeutic target in the treatment of drug‐resistant lymphomas. ( Cancer Sci 2012; 103: 34–41)