title: Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7.
abstract: Despite all the progress in cancer treatment, glioblastoma, the most malignant tumor of the central nervous system, remains a terminal disease and new therapeutic approaches are urgently needed. A combination of chemotherapy with modifications that lower the apoptotic threshold of cancer cells could be effective. Cathepsin L inhibition was suggested as one of such modifications but the mechanism of cathepsin L anti-apoptotic activity is largely unknown. In the present study we show that, in U87 glioblastoma cells, cathepsin L is present in the nucleus and regulates the transcription of effector caspases 3 and 7. In cells with low cathepsin L expression, p53 and prohibitin--transcription factors that regulate caspase 7 expression--accumulate in the nuclei. The importance of p53 in this process is highlighted by the fact that in U87 cells with inhibited p53 transcriptional activity or in p53-negative cells U251, cathepsin L inhibition did not influence caspase 7 expression and had minimal effect on the level of apoptosis. Since p53 pathways are often mutated in glioblastoma, the findings of our study need to be considered before using cathepsin L inhibition for glioblastoma therapy and suggest that such adjuvant therapy may be effective only for a subpopulation of p53 wild type glioblastoma patients.
authors.affiliation: Department of Genetic Toxicology and Cancer Biology, National Institue of Biology, Ljubljana, Slovenia. sasa.kenig@icgeb.org
authors.forename: Saša
authors.initials: S
authors.lastname: Kenig
authors.forename: Robert
authors.initials: R
authors.lastname: Frangež
authors.forename: Anja
authors.initials: A
authors.lastname: Pucer
authors.forename: Tamara
authors.initials: T
authors.lastname: Lah
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D010539:Permeability; D000091402:Prohibitins; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D000091402:Prohibitins; D012333:RNA, Messenger; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D056668:Cathepsin L