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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 20, 2005; DOI: 10.1124/jpet.105.089482

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Received for publication May 17, 2005.
Revised September 16, 2005.
Accepted for publication September 16, 2005.

Niemann-Pick C1 protein facilitates the efflux of the anticancer drug daunorubicin from cells according to a novel vesicle-mediated pathway

Yuping Gong 1, Muralikrishna Duvvuri 1, Michael Duncan 2, Jian Liu 2, Jeffrey P. Krise 1*

1 The University of Kansas 2 University of North Carolina at Chapel Hill

* Address correspondence to: E-mail: krise{at}ku.edu

Abstract

Niemann-Pick C1 (NPC1) is a late endosomal/lysosomal membrane protein originally reported on for its role in cholesterol trafficking in mammalian cells. NPC1 has been recently shown to share significant structural homology with a family of prokaryotic permeases and was proposed to play a role in intracellular drug transport; however, the mechanism for this has not been fully understood. We provide evidence here that is consistent with NPC1's involvement in a vesicle-mediated clearance of the anticancer agent daunorubicin from cells. In experiments with human fibroblasts, we demonstrate that lysosomal efflux of daunorubicin, as well as dextran molecules, are significantly reduced in cells with mutated and dysfunctional NPC1 compared to wild type fibroblasts. Furthermore, we show that NPC1 is implicated in a lysosomal drug sequestration phenotype exhibited by the multi-drug resistant (MDR) human leukemic HL-60 cancer cell line. Evaluations of cholesterol trafficking, NPC1 mRNA levels and protein expression are all consistent with a loss of NPC1 activity that is associated with the emergence of the MDR phenotype in this cell line. Collectively, this work proposes a novel role for NPC1 in a vesicle-mediated pathway responsible for the clearance of drugs from cells and provides an explanation for a drug sequestration phenotype exhibited by the MDR HL-60 cell line.


Key words: Niemann-Pick C1, cancer, daunorubicin, drug resistance, drug transport, lysosomes


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A. M. Kaufmann and J. P. Krise
Niemann-Pick C1 Functions in Regulating Lysosomal Amine Content
J. Biol. Chem., September 5, 2008; 283(36): 24584 - 24593.
[Abstract] [Full Text] [PDF]


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