Human cancer cells retain modest levels of enzymatically active matriptase only in extracellular milieu following induction of zymogen activation.

Abstract

The type 2 transmembrane serine protease matriptase is broadly expressed in human carcinomas and hematological cancers. The proteolytic activity of matriptase is a potential target of drugs and imaging probes. We assessed the fate of active matriptase following the induction of matriptase zymogen activation. Exposing eight human carcinoma cells to pH 6.0 buffer induced robust matriptase zymogen activation followed by rapid inhibition of the nascent active matriptase by hepatocyte growth factor activator inhibitor (HAI)-1. Consequently, no enzymatically active matriptase was detected in these cells. Some active matriptase is, however, rapidly shed to the extracellular milieu by these carcinoma cells. The lack of cell-associated active matriptase and the shedding of active matriptase were also observed in two hematological cancer lines. Matriptase shedding is correlated closely with the induction of matriptase activation, suggesting that matriptase activation and shedding are kinetically coupled. The coupling allows a proportion of active matriptase to survive HAI-1 inhibition by rapid shedding from cell surface. Our study suggests that cellular free, active matriptase is scarce and might not be an effective target for in vivo imaging and drug development.

• Authors: Li-Ling Chu, Yuan Xu, Jie-Ru Yang, Yi-An Hu, Hsiang-Hua Chang, Hong-Yu Lai, Chun-Che Tseng, Hue-Yu Wang, Michael D Johnson, Jehng-Kang Wang, Chen-Yong Lin
• Journal: PloS one (PLoS One) Vol. 9 Issue 3 Pg. e92244 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24663123 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Enzyme Precursors
• Serine Endopeptidases
• matriptase

Topics

• Cell Line, Tumor
• Enzyme Activation
• Enzyme Precursors (metabolism)
• Extracellular Space (enzymology, metabolism)
• Humans
• Neoplasms (enzymology, pathology)
• Serine Endopeptidases (metabolism)