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Lysosomal Cathepsin B Participates in the Podosome-Mediated Extracellular Matrix Degradation and Invasion via Secreted Lysosomes in v-Src Fibroblasts

¹ Eppley Institute for Research in Cancer and Allied Diseases, and UNMC-Eppley Cancer Center, ² Department of Biochemistry and Molecular Biology, College of Medicine, and ³ Department of Genetics, Cell Biology and Anatomy, College of Medicine, and UNMC-Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska; ⁴ Department of Pharmacology and Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan; ⁵ Divisions of Molecular Oncology and Cancer Biology, Evanston Northwestern Healthcare Research Institute, Department of Medicine, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, and Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois; and ⁶ Dana-Farber Cancer Institute, Boston, Massachusetts

Requests for reprints: Hamid Band, Eppley Institute, 986805 Nebraska Medical Center, Omaha, NE 68198-6805. Phone: 402-559-8572; Fax: 402-559-2823; E-mail: hband{at}unmc.edu.

Key Words: cathepsin B • invadopodia podosome • lysosome

Podosomes mediate cell migration and invasion by coordinating the reorganization of actin cytoskeleton and focal matrix degradation. MMP and serine proteases have been found to function at podosomes. The lysosomal cysteine cathepsins, a third major class of matrix-degrading enzymes involved in tumor invasion and tissue remodeling, have yet to be linked to podosomes with the exception of cathepsin K in osteoclasts. Using inhibitors and shRNA-mediated depletion, we show that cathepsin B participates in podosomes-mediated focal matrix degradation and invasion in v-Src–transformed fibroblasts. We observed that lysosomal marker LAMP-1 localized at the center of podosome rosettes protruding into extracellular matrix using confocal microscopy. Time-lapse live-cell imaging revealed that lysosomal vesicles moved to and fused with podosomes. Disruption of lysosomal pH gradient with Bafilomycin A1, chloroquine, or ammonium chloride greatly enhanced the formation of podosomes and increased the matrix degradation. Live-cell imaging showed that actin structures, induced shortly after Bafilomycin A1 treatment, were closely associated with lysosomes. Overall, our results suggest that cathepsin B, delivered by lysosomal vesicles, is involved in the matrix degradtion of podosomes. [Cancer Res 2008;68(22):9147–56]

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				Correction: Article on Lysosomal Cathepsin B Functions in Podosome Cancer Res., January 1, 2009; 69(1): 381 - 381. [Full Text] [PDF]