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Background. In our work, we investigated the role of ABC transporters and the transcription factor YB-1 protein in the formation of drug resistance to the proteasome inhibitor bortezomib in multiple myeloma.Materials and methods. We used the RPMI8226 and NCI-H929 cultures and their bortezomib-resistant sublines as models.Results. Two major ABC transporter proteins, P-glycoprotein and MRP1, are not involved in the emergence of resistance to bortezomib, moreover, bortezomib contributed to decrease of these genes expression. Expression of the MVP gene was increased only in the resistant RPMI8226/btz-6 variant, but not in H929/btz-6. The localization of the YB-1 protein, a transcription factor for the MDR1, MRP1 and MVP genes, changed only in RPMI8226/btz-6 cells, as well, it became diffuse in 20 % of the cells as compared to 7 % of the cells in the RPMI8226 parent line. The only ABC transporter gene, activated in both RPMI8226/btz-6 and H929/btz-6 sublines, was BCRP. Сross-resistance to doxorubicin is also shown for these sublines.Conclusion. Thus, the activation of ABC transporters is not a key mechanism for the formation of bortezomib drug resistance. MVP protein may play certain role, and an increase in the BCRP expression explains the emergence of resistance to doxorubicin, but not to bortezomib, since the latter is not a substrate of BCRP.

AbstractBackground: YB-1 is a multifunctional protein, a transcription factor involved in the regulation of numerous cellular processes. YB-1 is an important protein in molecular cascades that regulate the response to the presence of a pathogen, inflammatory activity, and the effectiveness of healing and cure. We believe that YB-1 may also play an important role in pulmonary tuberculosis. However, the YBX1 transcriptional activity and the role of the YB-1 protein in the pathogenesis of this disease have not yet been determined. The aim of the study was to identify the most significant correlations between the expression of the YB-1 protein gene, the genes of key cytokines involved in the regulation of tuberculous inflammation (IL-6, IL-10, INF-γ, TGF-β, TNF-α, IL-1β), the hypoxia factor HIF1a and the P-gp protein gene ABCB1 in pulmonary tuberculosis. Methods: Gene expression was determined by quantitative PCR in samples obtained from 35 patients. Correlation and cluster analysis were performed based on the PCR results. Results: A positive correlation was found between the expression of YBX1, TGFB1, and ABCB1 genes. The correlation between the expression of YBX1 and ABCB1 genes is moderate, while the expression of ABCB1 gene has a strong positive correlation with the HIF1A and IL6 genes. The strongest correlation was found between YBX1 and TGFB1 (r=0.62). There is no correlation of YBX1 with the genes of other cytokines. TGFB1 has a moderate correlation with TNF (r = 0.56). The relationship of YBX1 with TGFB1 was confirmed by cluster analysis, which demonstrates the formation of a single cluster of YBX1, TGFB1, TNF. Discussion and conclusion: we assume that the YBX1, TGFB1, TNF gene cluster forms a regulatory system that plays an important role in the development of tuberculous inflammation. Our work expands the knowledge on the molecular genetic characteristics of one of the forms of pulmonary tuberculosis - tuberculoma. We assume that the YB-1 protein can potentially have different functions: act as one of the participants in tuberculous inflammation through the effect on the expression of cytokines; modulate the P-gp activity and change the pharmacokinetics of anti-tuberculosis drugs, which requires further study.