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Endocytic Ark/Prk Kinases Play a Critical Role in Adriamycin Resistance in Both Yeast and Mammalian Cells

¹ Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan and ² Laboratory of Analytical Chemistry, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan

Requests for reprints: Akira Naganuma, Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan. Phone: 81-22-795-6870; Fax: 81-22-795-6869; E-mail: naganuma{at}mail.pharm.tohoku.ac.jp.

To elucidate the mechanism of acquired resistance to Adriamycin, we searched for genes that, when overexpressed, render Saccharomyces cerevisiae resistant to Adriamycin. We identified AKL1, a gene of which the function is unknown but is considered, nonetheless, to be a member of the Ark/Prk kinase family, which is involved in the regulation of endocytosis, on the basis of its deduced amino acid sequence. Among tested members of the Ark/Prk kinase family (Ark1, Prk1, and Akl1), overexpressed Prk1 also conferred Adriamycin resistance on yeast cells. Prk1 is known to dissociate the Sla1/Pan1/End3 complex, which is involved in endocytosis, by phosphorylating Sla1 and Pan1 in the complex. We showed that Akl1 promotes phosphorylation of Pan1 in this complex and reduces the endocytic ability of the cell, as does Prk1. Sla1- and End3-defective yeast cells were also resistant to Adriamycin and overexpression of Akl1 in these defective cells did not increase the degree of Adriamycin resistance, suggesting that Akl1 might reduce Adriamycin toxicity by reducing the endocytic ability of cells via a mechanism that involves the Sla1/Pan1/End3 complex and the phosphorylation of Pan1. We also found that HEK293 cells that overexpressed AAK1, a member of the human Ark/Prk family, were Adriamycin resistant. Our findings suggest that endocytosis might be involved in the mechanism of Adriamycin toxicity in yeast and human cells. (Cancer Res 2006; 66(24): 11932-7)