Abstract
Multidrug resistance protein-1 (MDR1) has been proven to be associated with the development of chemoresistance to imatinib (Glivec, STI571) which displays high efficacy in treatment of BCR-ABL-positive chronic myelogenous leukemia (CML). However, the possible mechanisms of MDR1 modulation in the process of the resistance development remain to be defined. Herein, galectin-1 was identified as a candidate modulator of MDR1 by proteomic analysis of a model system of leukemia cell lines with a gradual increase of MDR1 expression and drug resistance. Coincidently, alteration of galectin-1 expression triggers the change of MDR1 expression as well as the resistance to the cytotoxic drugs, suggesting that augment of MDR1 expression engages in galectin-1-mediated chemoresistance. Moreover, we provided the first data showing that NF-κB translocation induced by P38 MAPK activation was responsible for the modulation effect of galectin-1 on MDR1 in the chronic myelogenous leukemia cells. Galectin-1 might be considered as a novel target for combined modality therapy for enhancing the efficacy of CML treatment with imatinib.
Highlights
Formation of the BCR-ABL fusion gene coding for a constitutively active BCR-ABL tyrosine kinase via t(9;22)(q34;q11) reciprocal translocation initiates 95% of chronic myelogenous leukemia (CML), and 25% of adults and 5% of children acute lymphoblastic leukemia (ALL) [1]
Quantitative PCR (q-PCR) analysis showed that the expression level of Multidrug resistance protein-1 (MDR1) in the revertant K562/ ADM cells is less than the resistant K562/ADM cells, but higher than the sensitive ones, suggesting that the expression level of MDR1 gradually decreases during the course of cultivation in the absence of adriamycin (Figure 1)
The results imply that a gradual increase of resistance against adriamycin and imatinib is accompanied by a gradual increase of MDR1 level during the course of development of drug resistance in K562 cells exposed to adriamycin
Summary
Formation of the BCR-ABL fusion gene coding for a constitutively active BCR-ABL tyrosine kinase via t(9;22)(q34;q11) reciprocal translocation initiates 95% of chronic myelogenous leukemia (CML), and 25% of adults and 5% of children acute lymphoblastic leukemia (ALL) [1]. The occurrence of drug resistance was reported in CML patients with advanced stages treated with imatinib [3]. Amplification of the BCR-ABL gene and mutations of the kinase domain of ABL have been described as the molecular mechanisms for the development of imatinib resistance [4,5,6,7,8,9]. Overexpression or mutations of BCR-ABL could not explain all drug resistance to imatinib in CML patients, implying that the alternative mechanisms may exist [10,11,12]. We first applied proteomic approach to identify galectin-1 as a candidate of MDR1 modulators for mediating drug resistance in CML cells by comparison of the protein profiles among a model system of leukemia cell lines with a gradual increase of MDR1 expression and www.impactjournals.com/oncotarget drug resistance, and further explored the mechanisms of galectin-1 acting as a novel MDR1 modulator contributing to functional resistance against the cytotoxic drugs
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