Abstract
BackgroundChemoresistance remains a significant challenge in chronic myelogenous leukemia (CML) management, which is one of the most critical prognostic factors. Elucidation the molecular mechanisms underlying the resistance to chemoresistance may lead to better clinical outcomes.ResultsIn order to identify potential protein targets involved in the drug-resistant phenotype of leukemia, especially the chronic myelogenous leukemia (CML), we used a high-resolution “ultra-zoom” 2DE-based proteomics approach to characterize global protein expression patterns in doxorubicin-resistant myelogenous leukemia cells compared with parental control cells. Ultra-high resolution of 2DE was achieved by using a series of slightly overlapping narrow-range IPG strips during isoelectric focusing (IEF) separation. A total number of 44 proteins with altered abundances were detected and identified by MALDI-TOF or LC-MS/MS. Among these proteins, enolase, aldolase, HSP70 and sorcin were up-regulated in doxorubicin-resistant myelogenous leukemia cell line, whereas HSP27 was down-regulated. Some of the results have been validated by Western blotting. Both enolase and aldolase were first reported to be involved in chemoresistance, suggesting that process of glycolysis in doxorubicin-resistant myelogenous leukemia cells was accelerated to some extent to provide more energy to survive chemical stress. Possible roles of most of the identified proteins in development of chemoresistance in myelogenous leukemia cells were fully discussed. The results presented here could provide clues to further study for elucidating the mechanisms underlying drug resistance in leukemia.ConclusionsAs a whole, under the chemical stress, the doxorubicin-resistant myelogenous leukemia cells may employ various protective strategies to survive. These include: (i) pumping the cytotoxic drug out of the cells by P-glycoprotein, (ii) increased storage of fermentable fuel, (iii) sophisticated cellular protection by molecular chaperones, (iv) improved handling of intracellular calcium, (v) increased glucose utilization via increased rates of glycolysis. In the present study, proteomic analysis of leukemia cells and their drug resistant variants revealed multiple alterations in protein expression. Our results indicate that the development of drug resistance in doxorubicin-resistant myelogenous leukemia cells is a complex phenomenon undergoing several mechanisms.Electronic supplementary materialThe online version of this article (doi:10.1186/s12953-014-0057-y) contains supplementary material, which is available to authorized users.
Highlights
Chemoresistance remains a significant challenge in chronic myelogenous leukemia (CML) management, which is one of the most critical prognostic factors
Glutathione S transferase (GST) is another important protein found to be associated with multi-drug resistance (MDR) [3,4], of which the expression is often observed to be up-regulated in drug resistant cell lines
Cytotoxicity assay Cell proliferation assays for both K562/A02 and K562 cultured in the presence or absence of doxorubicin were performed to investigate the drug-resistance characteristics of K562/A02 cells, as well as the viability of K562 cells under chemical stress (Figure 1)
Summary
Chemoresistance remains a significant challenge in chronic myelogenous leukemia (CML) management, which is one of the most critical prognostic factors. Resistance to doxorubicin is often observed in patients with leukemia, resulting in failure in chemotherapy. Efforts have been made to reveal the molecular mechanisms underlying the development of chemoresistance, Qinghong et al Proteome Science (2015) 13:1 multi-drug resistance (MDR) in CML. Glutathione S transferase (GST) is another important protein found to be associated with MDR [3,4], of which the expression is often observed to be up-regulated in drug resistant cell lines. Accumulated evidence has shown that these proteins are involved in multiple different pathways and often interact with each other, indicating that the mechanisms mediating drug resistance in CML are multifaceted and still not clearly defined
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