1. ¹Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
2. ²Experimental Neuro-Oncology Group, Department of Neuropathology, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London, UK
3. ³Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
4. ⁴MRC Applied Neuroscience Group, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre Nottingham, UK
5. ⁵FACS Laboratory, London Research Institute, Lincoln's Inn Fields Laboratories, Cancer Research, 44 Lincoln's Inn Fields, London, UK
6. ⁶Department of Biochemical Research and Drug Design, Krka, d.d., Cesta na Brdo 49, Ljubljana, Slovenia

Correspondence: Dr Tamara T Lah, Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Vena Pot 111, Ljubljana 1000, Slovenia. E-mail: tamara.lah@uni-lj.si

Received 19 September 2002.

Abstract

Invasion and metastasis of certain tumors are accompanied by increased mRNA protein levels and enzymatic activity of cathepsin L. Cathepsin L has also been suggested to play a role in the proteolytic cascades associated with apoptosis. To investigate the role of cathepsin L in brain tumor invasion and apoptosis, the human glioma cell line, IPTP, was stably transfected with full-length antisense and sense cDNA of cathepsin L. Down-regulation of cathepsin L by antisense cDNA significantly impaired (up to 70%) glioma cell invasion in vitro and markedly increased glioma cell apoptosis induced by staurosporine. Compared to control and parental cell lines, antisense down-regulation of cathepsin L was associated with an earlier induction of caspase-3 activity. Up-regulation of cathepsin L activity by sense cDNA was associated with reduced apoptosis and later induction of caspase-3 activity. Moreover, down-regulation of cathepsin L lowered the expression of antiapoptotic protein Bcl-2, whereas up-regulation increased the expression of Bcl-2, indicating that cathepsin L acts upstream of caspase-3. These data show that cathepsin L is an important protein mediating the malignancy of gliomas and its inhibition may diminish their invasion and lead to increased tumor cell apoptosis by reducing apoptotic threshold.