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High-Copy Overexpression Screening Reveals PDR5 as the Main Doxorubicin Resistance Gene in Yeast
Ayse Banu Demir1,2, Ahmet Koc1
1Izmir Institute of Technology, Department of Molecular Biology and Genetics, Urla, Izmir, Turkey.
Abstract:
Doxorubicin is one of the most potent anticancer drugs used in the treatment of various cancer types. The efficacy of doxorubicin is influenced by the drug resistance mechanisms and its cytotoxicity. In this study, we performed a high-copy screening analysis to find genes that play a role in doxorubicin resistance and found several genes (CUE5, AKL1, CAN1, YHR177W and PDR5) that provide resistance. Among these genes, overexpression of PDR5 provided a remarkable resistance, and deletion of it significantly rendered the tolerance level for the drug. Q-PCR analyses suggested that transcriptional regulation of these genes was not dependent on doxorubicin treatment. Additionally, we profiled the global expression pattern of cells in response to doxorubicin treatment and highlighted the genes and pathways that are important in doxorubicin tolerance/toxicity. Our results suggest that many efflux pumps and DNA metabolism genes are upregulated by the drug and required for doxorubicin tolerance.
Insights
This study identifies key genes, including PDR5, involved in doxorubicin resistance. Understanding these mechanisms is crucial for improving cancer treatment efficacy and managing drug resistance.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Doxorubicin is a potent anticancer drug with efficacy limited by drug resistance and cytotoxicity.
- Understanding the genetic basis of doxorubicin resistance is critical for enhancing therapeutic outcomes.
Purpose of the Study:
- To identify genes conferring resistance to doxorubicin using high-copy screening.
- To elucidate the role of specific genes in doxorubicin tolerance and toxicity.
- To analyze global gene expression patterns in response to doxorubicin treatment.
Main Methods:
- High-copy screening to identify resistance genes.
- Quantitative PCR (Q-PCR) for transcriptional analysis.
- Global gene expression profiling.
Main Results:
- Several genes (CUE5, AKL1, CAN1, YHR177W, PDR5) were identified as conferring doxorubicin resistance.
- Overexpression of PDR5 significantly increased resistance, while its deletion decreased tolerance.
- Transcriptional regulation of identified genes was independent of doxorubicin treatment.
- Doxorubicin treatment upregulated efflux pumps and DNA metabolism genes, essential for tolerance.
Conclusions:
- PDR5 plays a significant role in doxorubicin resistance.
- Upregulation of efflux pumps and DNA metabolism genes is vital for cellular tolerance to doxorubicin.
- These findings provide insights into doxorubicin resistance mechanisms and potential therapeutic targets.
