Abstract
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.
© 2011 Japanese Cancer Association.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents, Phytogenic / pharmacology
-
Apoptosis / drug effects*
-
Blotting, Western
-
Camptothecin / analogs & derivatives
-
Camptothecin / pharmacology
-
Drug Resistance, Neoplasm / drug effects
-
Drug Resistance, Neoplasm / genetics*
-
Etoposide / pharmacology
-
Gene Expression Regulation, Neoplastic / drug effects*
-
Humans
-
Inhibitor of Apoptosis Proteins / chemistry*
-
Inhibitor of Apoptosis Proteins / genetics
-
Inhibitor of Apoptosis Proteins / metabolism*
-
Irinotecan
-
Lymphoma, B-Cell / drug therapy
-
Lymphoma, B-Cell / genetics*
-
Lymphoma, B-Cell / metabolism
-
Nuclear Proteins / antagonists & inhibitors
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism*
-
Organoplatinum Compounds / pharmacology
-
Oxaliplatin
-
Polycomb Repressive Complex 1
-
Proto-Oncogene Proteins / antagonists & inhibitors
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism*
-
RNA, Messenger / genetics
-
RNA, Small Interfering / genetics
-
Repressor Proteins / antagonists & inhibitors
-
Repressor Proteins / genetics
-
Repressor Proteins / metabolism*
-
Reverse Transcriptase Polymerase Chain Reaction
-
Survivin
-
Tumor Cells, Cultured
Substances
-
Antineoplastic Agents
-
Antineoplastic Agents, Phytogenic
-
BIRC5 protein, human
-
BMI1 protein, human
-
Inhibitor of Apoptosis Proteins
-
Nuclear Proteins
-
Organoplatinum Compounds
-
Proto-Oncogene Proteins
-
RNA, Messenger
-
RNA, Small Interfering
-
Repressor Proteins
-
Survivin
-
Oxaliplatin
-
Etoposide
-
Irinotecan
-
Polycomb Repressive Complex 1
-
Camptothecin