Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels

Navab, Roya; Pedraza, Claudio E.; Fallavollita, Lucia; Wang, N; Chevet, Éric; Auguste, Patrick; Jenna, Sarah; You, Zhipeng; Bikfalvi, Andréas; O’Connor, Rosemary; Erickson, Ann H.; Mort, John S.; Brodt, Pnina

doi:10.1038/onc.2008.144

Cited by 30 publications

(16 citation statements)

References 58 publications

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“…CatL inhibition has been shown to be the cause of loss of responsiveness to IGF-I [40], which was associated with an increase in spontaneous apoptosis. CatL also degrades CatD [41], another lysosomal protease that mediates apoptosis [42].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7

et al. 2011

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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.

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Section: Discussionmentioning

confidence: 99%

Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7

et al. 2011

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“…In contrast, Urbich et al showed that Ctsl is actually critical for the invasive capacity of endothelial progenitor cells, promoting neovascularization (Urbich et al , 2005). Intracellular Ctsl has been identified as a positive regulator of insulin-like growth factor 1 receptor signaling and of the experimental metastasis of tumor cells, which are dependent on insulin-like growth factor 1 receptor, and has also been found to have a role in promoting resistance toward chemotherapeutic drugs (Zheng et al , 2004; Navab et al , 2008). N-terminally truncated Ctsl has been found in the nucleus, in which it activates the CDP/Cux transcription factor, a positive regulator of the cell cycle involved in cellular transformation (Goulet et al , 2007).…”

Section: Introductionmentioning

confidence: 99%

Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis

et al. 2009

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To define a functional role for the endosomal/lysosomal cysteine protease cathepsin L (Ctsl) during squamous carcinogenesis, we generated mice harboring a constitutive Ctsl deficiency in addition to epithelial expression of the human papillomavirus type 16 oncogenes (human cytokeratin 14 (K14)–HPV16).We found enhanced tumor progression and metastasis in the absence of Ctsl. As tumor progression in K14–HPV16 mice is dependent on inflammation and angiogenesis, we examined immune cell infiltration and vascularization without finding any effect of the Ctsl genotype. In contrast, keratinocyte-specific transgenic expression of cathepsin V, the human orthologue of mouse Ctsl, in otherwise Ctsl-deficient K14–HPV16 mice restored the phenotype observed in the control HPV16 skin. To better understand this phenotype at the molecular level, we measured several oncogenic signal transduction pathways in primary keratinocytes on stimulation with keratinocyte-conditioned cell culture medium. We found increased activation of protein kinase B/Akt and mitogen-activated protein kinase pathways in protease-deficient cells, especially if treated with media conditioned by Ctsl-deficient keratinocytes. Similarly, the level of active GTP-Ras was increased in Ctsl-deficient epidermis. We conclude that Ctsl is critical for the termination of growth factor signaling in the endosomal/lysosomal compartment of keratinocytes and, therefore, functions as an anti-tumor protease.

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“…Recombinant CTLA-2α selectively inhibits cathepsin L-like cysteine proteinases, papain-like proteases of animal tissues [13]. Cathepsin L affects the immune system [27, 28] but it is not clear if it is pro- or anti-apoptotic [29–31]. We find that cAMP/PKA up-regulates cathepsin L activity but over-expression of CTLA-2α does not change its activity; thus, increased cathepsin L activity does not explain cAMP/PKA-promoted apoptosis in S49 cells.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic T lymphocyte antigen-2 alpha induces apoptosis of murine T-lymphoma cells and cardiac fibroblasts and is regulated by cAMP/PKA

Zhang

Yun

Murray

et al. 2011

Cellular Signalling

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The mechanism of cAMP-promoted apoptosis is not well defined. In wild-type (WT) murine S49 lymphoma cells, cAMP promotes apoptosis in a protein kinase A (PKA)-dependent manner. We find that treatment of WT S49 cells with 8-CPT-cAMP prominently increases the expression (as determined by DNA microarray analysis, real-time PCR and immunblotting) of cytotoxic T lymphocyte antigen-2α (CTLA-2α), a cathepsin L-like cysteine protease inhibitor. By contrast, CTLA-2α expression is only slightly increased by 8-CPT-cAMP treatment of D- S49 cells, which lack cAMP/PKA-promoted apoptosis. Raising endogenous cAMP (by use of forskolin or inhibition of phosphodiesterase [PDE] 4) or a PKA-selective, but not an Epac-selective, cAMP analogue, increases CTLA-2α mRNA expression; PKA, and not Epac, thus mediates the increase in CTLA-2α expression. An adenoviral CLTA-2α (Ad-CTLA-2α) construct induces apoptosis and enhances cAMP-promoted apoptosis in WT S49 cells but such cells do not have an increase in cathepsin L activity nor does a cathepsin L inhibitor alter cAMP-promoted apoptosis. 8-CPT-cAMP also increases CTLA-2α expression and induces apoptosis in murine cardiac fibroblasts; knockdown of CTLA-2α expression by siRNA blocks 8-CPT-cAMP-promoted apoptosis. Thus, cAMP increases CTLA-2α expression in murine lymphoma and cardiac fibroblasts and this increase in CTLA-2α contributes to cAMP/PKA-promoted apoptosis by mechanisms that are independent of the ability of CTLA-2α to inhibit cathepsin L.

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Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels

Cited by 30 publications

References 58 publications

Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7

Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7

Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis

Cytotoxic T lymphocyte antigen-2 alpha induces apoptosis of murine T-lymphoma cells and cardiac fibroblasts and is regulated by cAMP/PKA

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