Research

Cathepsin X inhibitors impair the resistence of tumor cells to antiprotease therapy

Code:

J4-8227

Range:

01. May 2017 - 30. April 2020

Range:

0,47 FTE

Leader:

Janko Kos

Field:

4.06.01 Biotechnical sciences-Biotechnology-Recombinant DNA technology

Abstract:

The progression of malignant diseases is associated with excessive activity of the proteolytic enzymes involved in tumor growth, angiogenesis, migration, invasion and metastasis. Among them is a group of cysteine cathepsins that are present in normal cells in endosomes and lysosomes and are responsible for intracellular protein catabolism. In tumor cells these enzymes undergo various changes regarding their expression, activity and localization. Cathepsin B has appeared as the most important tumor promoter. In lysosomes it acts predominantly as an exopeptidase (carboxypeptidase) involved in protein catabolism and autophagy, whereas in tumors, with increased endopeptidase activity, it is responsible for degrading proteins of the extracellular matrix (ECM). Cathepsin B is overexpressed in practically all tumor types and inhibition of its endopeptidase activity has frequently been reported to reduce tumor growth and metastasis in animal cancer models. In recent years, several specific inhibitors of cathepsin B with favorable pharmacological properties have been developed and become candidates for clinical testing. They provide very potent antitumor effects although, after a time, their effectiveness is reduced. We and others have recently found that the main factor of this resistance is delayed over-expression of a similar proteolytic enzyme, cathepsin X. Like cathepsin B, cathepsin X also acts as a carboxypeptidase. However, in tumors it does not switch to endopeptidase activity to degrade the ECM but enhances tumor cell migration and invasion by alternative mechanisms, predominantly through the regulation of integrin receptors and tumor suppressor protein profilin 1. Its higher expression and activity is therefore associated with the renewed ability of tumor cells to migrate and invade, although in this case without degradation of the ECM.