Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7
- 334 Downloads
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.
KeywordsCathepsin L Apoptosis Glioblastoma Caspase 3 Caspase 7 P53
The work was supported by Slovenian Research Agency, Programme #P-0105-0245 (granted to TTL), and Young Researcher Project (granted to SK). The authors are thankful to Dr. Viktor Menart for human recombinant TNFα, Dr. Janko Kos for cathepsin L antibody and ELISA assay, Dr. Nobuhiko Katunuma for cathepsin L inhibitor Clik 148 and Dr. Bernd Wiederanders for the DNA-microarray.
Conflict of interest
The authors declare that they have no conflict of interest.
- 12.Lankelma JM, Voorend DM, Barwari T, Koetsveld J, Van der Spek AH, De Porto AP, Van Rooijen G et al (2010) Cathepsin L, target in cancer treatment? Life Sci 86:225–233Google Scholar
- 18.Torsvik A, Rosland GV, Svendsen A, Molven A, Immervoll H, McCormack E, Lonning PE et al (2010) Spontaneous malignant transformation of human mesenchymal stem cells reflects cross-contamination: putting the research field on track—letter. Cancer Res 70:6393–6396Google Scholar
- 21.Pucer A, Castino R, Mirkovic B, Falnoga I, Slejkovec Z, Isidoro C, Lah TT (2010) Differential role of cathepsins B and L in autophagy-associated cell death induced by arsenic trioxide in U87 human glioblastoma cells. Biol Chem 391:519–531Google Scholar
- 38.Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60:166–193Google Scholar
- 39.Huse JT, Holland EC (2010) Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer 10:319–331Google Scholar