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

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

International journal of cancer (2013-10-30)
Rebekka Kubisch, Thomas Fröhlich, Georg J Arnold, Laura Schreiner, Karin von Schwarzenberg, Andreas Roidl, Angelika M Vollmar, Ernst Wagner
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cathepsin B from human placenta, lyophilized powder, ≥5 units/mg protein
Sigma-Aldrich
Cathepsin B from human liver, buffered aqueous solution, ≥1,500 units/mg protein (E1%/280)
Sigma-Aldrich
Cathepsin B from bovine spleen, lyophilized powder, ≥10 units/mg protein