アドリアマイシンに対する感受性決定に係わる遺伝子群の検索及びその作用機構解析

抄録

  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.