Abstract
Doxorubicin is an anthracycline antibiotic that is among one of the most commonly used chemotherapeutic agents in the clinical setting. The usage of doxorubicin is faced with many problems including severe side effects and chemoresistance. To overcome these challenges, it is important to gain an understanding of the underlying molecular mechanisms with regards to the mode of action of doxorubicin. To facilitate this aim, we identified the genes that are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe. We further demonstrated interplay between factors controlling various aspects of chromosome metabolism, mitochondrial respiration and membrane transport. In the nucleus we observed that the subunits of the Ino80, RSC, and SAGA complexes function in the similar epistatic group that shares significant overlap with the homologous recombination genes. However, these factors generally act in synergistic manner with the chromosome segregation regulator DASH complex proteins, possibly forming two major arms for regulating doxorubicin resistance in the nucleus. Simultaneous disruption of genes function in membrane efflux transport or the mitochondrial respiratory chain integrity in the mutants defective in either Ino80 or HR function resulted in cumulative upregulation of drug-specific growth defects, suggesting a rewiring of pathways that synergize only when the cells is exposed to the cytotoxic stress. Taken together, our work not only identified factors that are required for survival of the cells in the presence of doxorubicin but has further demonstrated that an extensive molecular crosstalk exists between these factors to robustly confer doxorubicin resistance.
Highlights
Doxorubicin (DOXO)(trade name adriamycin) is an anthracycline antibiotic that ranks among the most useful anti-neoplastic agents used against a wide range of cancers including that of breast, prostrate, oesophageal, stomach, liver; sarcomas and hematological malignancies [1,2]
To find genes essential for chemoresistance against doxorubicin (DOXO), we began by examining the cytotoxicity of DOXO on fission yeast cell
Together with the epistatic relationship between the SWI/SNF ATP-dependent chromatin remodeling Ino80, SAGA histone acetyltransferase and RSC complexes with the homologous recombination (HR) proteins, we propose a model in which nucleosome remodeling and establishment of opened chromatin conformation via histone acetylation facilitate repair of DOXO adducts by HR factors and Ino80 complex probably during S-phase
Summary
Doxorubicin (DOXO)(trade name adriamycin) is an anthracycline antibiotic that ranks among the most useful anti-neoplastic agents used against a wide range of cancers including that of breast, prostrate, oesophageal, stomach, liver; sarcomas and hematological malignancies [1,2]. A major challenge in the usage of DOXO lies in the control of the administration dose as increase dosage heightens the propensity of adverse drug-linked cytotoxic effect, especially cardiotoxicity [1,2]. Another problem in DOXO usage is the rapid development of resistance by the cancer cells [6]. An understanding of the basic mechanisms employed by cells to resist the ill effects of DOXO is essential to fine-tune drug usage to achieve maximum killing of malignant cells yet minimizing cytotoxic side effects
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