Alterations in the expression of cytochrome c oxidase subunits in doxorubicin-resistant leukemia K562 cells.

Doxorubicin (DOX), a widely used antitumoral drug, induces numerous modifications in sensitive cells, interacting with nuclear and mitochondrial DNA. In previous studies achieved in two K562 DOX-resistant sublines (K562/0.2R and K562/0.5R), we have shown stable mitochondrial damage comparatively with sensitive parental cells, such as decrease of cytochrome c oxidase activity (COX; EC 1.9.3.1) and cytochrome aa3 content. In order to explain these data, we have studied several COX genes and their expression, in relationship with altered COX activity and multidrug resistance (MDR) phenotype. We have observed a lower expression of the catalytic subunits COX I and II in MDR sublines, which was neither related to mutations in the corresponding mitochondrial genes, nor to a reduced transcription rate. In contrast, we have noticed an increase in both MDR K562 variants, in the mRNA expression of the catalytic subunit COX III, related to an increase in the half-life of these transcripts. Moreover, the doxorubicin resistance phenotype in K562 cells was accompanied by modifications of the expression and steady-state mRNA levels of several nuclear-encoded regulatory COX subunits. Thus, doxorubicin-resistant K562 cells represent an interesting model to study stable modifications concomitant to MDR phenotype. Our results seem to indicate compensatory mechanisms which highlight the complexity of regulatory systems of COX enzyme, involving coordinate regulation of both nuclear and mitochondrial subunit expression.