HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 38, 39982-39988, September 17, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/38/39982    most recent M406698200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kokkonen, N. Articles by Kellokumpu, S. Search for Related Content PubMed PubMed Citation Articles by Kokkonen, N. Articles by Kellokumpu, S. Social Bookmarking                      What's this?

Defective Acidification of Intracellular Organelles Results in Aberrant Secretion of Cathepsin D in Cancer Cells^*

Nina Kokkonen, Antti Rivinoja, Annika Kauppila, Marko Suokas, Ilmo Kellokumpu, and Sakari Kellokumpu¶

From the Department of Biochemistry, University of Oulu, P. O. Box 3000, FIN-90014 Oulu, Finland and Jyväskylä Central Hospital, Jyväskylä, Keskussairaalantie 19, FIN-40620 Jyväskylä, Finland

Aberrant secretion of lysosomal hydrolases such as (pro)cathepsin D (proCD) is a common phenotypic change in many human cancers. Here we explore the underlying molecular defect(s) and find that MCF-7 breast and CaCo-2 colorectal cancer cells that are unable to acidify their endosomal compartments secreted higher amounts of proCD than did acidification-competent cancer cell types. The latter secreted equivalent amounts of proCD only after dissipation of their organellar pH gradients with NH₄Cl. Assessing the critical steps that resulted in proCD secretion revealed that the Golgi-associated sorting receptor for CD, i.e. the cation-independent mannose-6-phosphate receptor (MPR300), was aberrantly distributed in acidification-defective MCF-7 cells. It accumulated mainly in late endosomes and/or lysosomes as a complex with its ligand (proCD or intermediate CD), as evidenced by its co-localization with both CD and LAMP-2, a late endosome/lysosome marker. Our immunoprecipitation analyses also showed that MCF-7 cells possessed 7-fold higher levels of receptor-enzyme complexes than did acidification-competent cells. NH₄Cl induced similar receptor redistribution into LAMP-2-positive structures in acidification-competent cells but not in MCF-7 cells. The receptor also recovered its normal Golgi localization upon drug removal. Based on these observations, we conclude that defective acidification results in the aberrant secretion of proCD in certain cancer cells and interferes mainly with the normal disassembly of the receptor-enzyme complexes and efficient receptor reutilization in the Golgi.

Received for publication, June 16, 2004

^* The study was supported by grants from The Academy of Finland and The Central Hospital of Jyväskylä. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Fax: 358-8-5531141; E-mail: sakari.kellokumpu{at}oulu.fi.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. G. W. Norden, Sharon. C. Gardner, W. van't Hoff, and R. J. Unwin Lysosomal enzymuria is a feature of hereditary Fanconi syndrome and is related to elevated CI-mannose-6-P-receptor excretion Nephrol. Dial. Transplant., September 1, 2008; 23(9): 2795 - 2803. [Abstract] [Full Text] [PDF]

				Z. Jevnikar, N. Obermajer, M. Bogyo, and J. Kos The role of cathepsin X in the migration and invasiveness of T lymphocytes J. Cell Sci., August 15, 2008; 121(16): 2652 - 2661. [Abstract] [Full Text] [PDF]

				F. Okamoto, H. Kajiya, K. Toh, S. Uchida, M. Yoshikawa, S. Sasaki, M. A. Kido, T. Tanaka, and K. Okabe Intracellular ClC-3 chloride channels promote bone resorption in vitro through organelle acidification in mouse osteoclasts Am J Physiol Cell Physiol, March 1, 2008; 294(3): C693 - C701. [Abstract] [Full Text] [PDF]

				W. Li, C. Marshall, L. Mei, J. Gelfand, and J. T. Seykora Srcasm Corrects Fyn-induced Epidermal Hyperplasia by Kinase Down-regulation J. Biol. Chem., January 12, 2007; 282(2): 1161 - 1169. [Abstract] [Full Text] [PDF]

				O. C. Probst, P. Ton, B. Svoboda, A. Gannon, W. Schuhmann, J. Wieser, R. Pohlmann, and L. Mach The 46-kDa mannose 6-phosphate receptor does not depend on endosomal acidification for delivery of hydrolases to lysosomes J. Cell Sci., December 1, 2006; 119(23): 4935 - 4943. [Abstract] [Full Text] [PDF]

				C. Czupalla, H. Mansukoski, T. Riedl, D. Thiel, E. Krause, and B. Hoflack Proteomic Analysis of Lysosomal Acid Hydrolases Secreted by Osteoclasts: Implications for Lytic Enzyme Transport and Bone Metabolism Mol. Cell. Proteomics, January 1, 2006; 5(1): 134 - 143. [Abstract] [Full Text] [PDF]