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Journal of Biochemistry Advance Access originally published online on December 19, 2006
Journal of Biochemistry 2007 141(2):239-250; doi:10.1093/jb/mvm030
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© 2006 The Japanese Biochemical Society.

Decrease of Cholesterol in Mouse Melanoma Causes Secretion of Lysosomal Enzymes

Akihiro Michihara*, Ken Toda, Michihisa Suenobu, Kenji Akasaki and Hiroshi Tsuji

Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

*To whom correspondence should be addressed: Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan. E-mail: mitihara{at}fupharm.fukuyama-u.ac.jp

Received February 21, 2006; Accepted December 8, 2006


  Abstract

We examined the change in the subcellular distribution of a lysosomal enzyme, ß-glucuronidase (ß-G), caused by decreased cholesterol levels in mouse melanoma cells using an HMG-CoA reductase inhibitor, lovastatin and lipoprotein-deficient serum (LDS). There was a decrease in the cholesterol content of the cells and increased secretion of the mature form of ß-G located in lysosomes, as documented by Percoll density gradient fractionation, digitonin permeabilization and immunoprecipitation. Furthermore, another lysosomal enzyme, cathepsin H, was found to be released in the medium from cells treated with lovastatin. Both the precursor and mature forms of cathepsin H were detected in the medium of treated cells. Next, when cells were treated with LDS without lovastatin, concomitantly with the decrease in the levels of cholesterol and ß-G activity in the cells, ß-G activity in the medium increased. Also, the ratio of ß-G (3.2-fold) released in the medium from cells treated with Dulbecco's modified Eagle medium (D-MEM) containing lovastatin and LDS was higher than that (2.3-fold) on treatment with D-MEM containing LDS without lovastatin. From these results, it was suggested that the exocytosis of mature enzymes from lysosomes into the medium or mis-sorting of the lysosomal precursor forms to the medium was caused by the lovastatin- and/or LDS-induced decrease in the cholesterol content of the cells, although the mechanism of secretion by lysosomal enzymes differed somewhat.

Key Words: ß-glucuronidase, cathepsin H, exocytosis, lysosome, melanoma, mis-sorting, mouse


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