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Published on: September 17, 2020
[A screen for genes involved in adriamycin resistance in Saccharomyces cerevisiae]
1Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. ttsutomu@m.tohoku.ac.jp
Abstract:
Adriamycin is an anthracycline antibiotic that is widely used in the treatment of various cancers. However, the efficacy of adriamycin-based chemotherapy is compromised by the development of adverse effects and the emergence of adriamycin-resistant cancer cells. In a search for novel mechanisms of resistance to adriamycin, we searched for genes that are related to adriamycin resistance using the budding yeast Saccharomyces cerevisiae and identified several genes (Akl1, Bsd2, Ssl2 and Erg13, etc.). We investigated the role of Akl1, a member of Ark/Prk kinase family, in adriamycin resistance and found that Akl1 might reduce adriamycin toxicity by inhibition of the internalization step in endocytosis via phosphorylation of component of endocytic complex. Furthermore, defects in vesicle trafficking from endoplasmic reticulum (ER) to vacuole reduced the degree of the adriamycin resistance induced by Akl1-overexpression, suggesting that inhibition of internalization step in endocytosis facilitates transport of protein from ER to vacuole, and decreases adriamycin toxicity.
Insights
Researchers identified Akl1, a kinase, which may reduce adriamycin toxicity by inhibiting endocytosis. This mechanism enhances adriamycin resistance by improving protein transport and reducing drug toxicity in cancer cells.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Adriamycin (doxorubicin) is a vital chemotherapy drug, but its effectiveness is limited by cancer cell resistance and adverse effects.
- Understanding novel mechanisms of adriamycin resistance is crucial for improving cancer treatment strategies.
Purpose of the Study:
- To identify novel genes involved in adriamycin resistance using Saccharomyces cerevisiae.
- To investigate the specific role of the Ark/Prk kinase family member, Akl1, in adriamycin resistance and its underlying mechanism.
Main Methods:
- Utilized Saccharomyces cerevisiae as a model organism to screen for genes conferring adriamycin resistance.
- Investigated the function of Akl1 in adriamycin resistance, focusing on its potential role in endocytosis and protein trafficking.
- Examined the impact of endocytic inhibition and endoplasmic reticulum (ER) to vacuole vesicle trafficking on adriamycin resistance.
Main Results:
- Identified several genes, including Akl1, associated with adriamycin resistance in yeast.
- Demonstrated that Akl1 may confer adriamycin resistance by inhibiting the internalization step of endocytosis through phosphorylation of endocytic components.
- Observed that impaired vesicle trafficking from the ER to the vacuole diminishes Akl1-mediated adriamycin resistance.
Conclusions:
- Akl1 plays a significant role in adriamycin resistance, potentially by modulating endocytosis.
- Inhibition of endocytosis by Akl1 appears to facilitate ER-to-vacuole protein transport, thereby decreasing adriamycin toxicity.
- These findings suggest a novel therapeutic strategy targeting endocytosis and protein trafficking pathways to overcome adriamycin resistance in cancer.
