V-ATPase inhibition by archazolid leads to lysosomal dysfunction resulting in impaired cathepsin B activation in vivo.

Abstract

The myxobacterial agent archazolid inhibits the vacuolar proton pump V-ATPase. V-ATPases are ubiquitously expressed ATP-dependent proton pumps, which are known to regulate the pH in endomembrane systems and thus play a crucial role in endo- and exocytotic processes of the cell. As cancer cells depend on a highly active secretion of proteolytic proteins in order to invade tissue and form metastases, inhibition of V-ATPase is proposed to affect the secretion profile of cancer cells and thus potentially abrogate their metastatic properties. Archazolid is a novel V-ATPase inhibitor. Here, we show that the secretion pattern of archazolid treated cancer cells includes various prometastatic lysosomal proteins like cathepsin A, B, C, D and Z. In particular, archazolid induced the secretion of the proforms of cathepsin B and D. Archazolid treatment abrogates the cathepsin B maturation process leading to reduced intracellular mature cathepsin B protein abundance and finally decreased cathepsin B activity, by inhibiting mannose-6-phoshate receptor-dependent trafficking. Importantly, in vivo reduced cathepsin B protein as well as a decreased proteolytic cathepsin B activity was detected in tumor tissue of archazolid-treated mice. Our results show that inhibition of V-ATPase by archazolid reduces the activity of prometastatic proteases like cathepsin B in vitro and in vivo.

• Authors: Rebekka Kubisch, Thomas Fröhlich, Georg J Arnold, Laura Schreiner, Karin von Schwarzenberg, Andreas Roidl, Angelika M Vollmar, Ernst Wagner
• Journal: International journal of cancer (Int J Cancer) Vol. 134 Issue 10 Pg. 2478-88 (May 15 2014) ISSN: 1097-0215 [Electronic] United States
• PMID: 24166050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 UICC.

Chemical References

• ATP6V0C protein, human
• Macrolides
• Receptor, IGF Type 2
• Thiazoles
• archazolid B
• cation-dependent mannose-6-phosphate receptor
• Cathepsin B
• Vacuolar Proton-Translocating ATPases

Topics

• Animals
• Blotting, Western
• Cathepsin B (genetics, metabolism)
• Cell Line, Tumor
• Enzyme Activation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lysosomes (drug effects, enzymology)
• MCF-7 Cells
• Macrolides (pharmacology)
• Mice
• Mice, Inbred BALB C
• Neoplasms (genetics, metabolism, pathology)
• Neoplasms, Experimental (genetics, metabolism, prevention & control)
• Protein Transport (drug effects)
• RNA Interference
• Receptor, IGF Type 2 (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Thiazoles (pharmacology)
• Tumor Burden (drug effects)
• Vacuolar Proton-Translocating ATPases (antagonists & inhibitors, genetics, metabolism)