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.

Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumours

“…For example, Reinheckel et al (2012) demonstrated that cathepsin L possesses tumour suppressor anti-proliferative activity in the Rip1-Tag2 mouse model, but enhances tumorigenesis in APC min and K14-HPV16 mice. We found that in glioblastoma cathepsin L upregulation has an anti-apoptotic effect by increasing caspase 3 synthesis (Kenig et al, 2011), supporting earlier reports that cathepsin L facilitates drug resistance (Lankelma et al, 2010).…”

“…Cytokine-regulated activity of cathepsin L ( Lankelma et al, 2010;Kenig et al, 2011) and cathepsin B (Bruchard et al, 2013) has been reported to be important in the development of chemo-resistance. It has been also shown (Tuomela et al, 2013) that cancer cells take DNA from dead cancer cells, killed by chemo-therapy, inducing expression of Toll-like receptor TLR9.…”

Andrographolide Induces Apoptosis of C6 Glioma Cells via the ERK-p53-Caspase 7-PARP Pathway

“…The promoter region of caspase 7 is known to contain a binding site for p53 [38]. Further, p53 activation has been shown to lead to downstream activation of caspases 3 and 7, causing apoptosis in human glioblastoma cells [39]. First, we want to examine whether p53 is activated under AND treatment.…”

Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy

“…Kenig et al partially revealed the mechanism of this apoptotic induction, demonstrating that CTSL inhibition lowers the apoptotic threshold of glioblastoma cells by upregulating p53 and caspase 3/7 expression (20).…”