Hypoxia Alters Cathepsin B / Inhibitor Profiles in Oral Carcinoma Cell Lines

Background: The tumor microenvironment is believed to contribute to the malignant properties of tumor cells in heterogeneous tumor tissues. We investigated the impact of hypoxia (1% oxygen) on the expression of cathepsin B and its natural inhibitors cystatin B and C. Materials and Methods: Patient-matched oral carcinoma cell lines from primary tumor and lymph node metastasis were used to study the effects of hypoxia on proliferation, protein expression, and proteolytic and inhibitor activities. Results: Hypoxic growth led to elevated cathepsin B expression and activity, and this effect was greater in metastatic than in primary tumor cells. Also, hypoxia led to down-regulation of the inhibitors cystatin C and B, resulting in increased residual activity of cathepsin B. Conclusion: These data suggest that the invasive and/or metastatic potential of cells may be enhanced under hypoxia by increasing cathepsin-mediated proteolysis. The results provide strong evidence for the involvement of cathepsin B and its cystatin inhibitors in hypoxia-enhanced tumor progression.