Cysteine Cathepsins and Cystatins as Cancer Biomarkers

Lah, Tamara T.; Obermajer, Nataša; Alonso, María Beatriz Durán; Kos, Janko

doi:10.1007/978-0-387-69057-5_29

Cited by 12 publications

(15 citation statements)

References 111 publications

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“…CatB inhibitors alone have been suggested as anticancer drugs owing to their potential effects to impair cell invasion, tumor growth and angiogenesis (Lah and Kos, 1998;Joyce et al, 2004;Lah et al, 2008). Notably, this is the first report on arsenite, as an effective, irreversible inhibitor of cellular and recombinant protein activity of CatB.…”

Section: Discussionmentioning

confidence: 87%

“…Among them, cathepsins L and B (CatL and CatB) are widely studied in association with cancer progression (Lah and Kos, 1998;Joyce et al, 2004;Lah et al, 2008). Both have also been shown to be overexpressed in high grade compared to low grade brain tumors and elevated CatB has been shown to correlate with shorter survival of patients (Strojnik et al, 1999(Strojnik et al, , 2005(Strojnik et al, , 2006(Strojnik et al, , 2007.…”

Section: Introductionmentioning

confidence: 96%

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Differential role of cathepsins B and L in autophagy-associated cell death induced by arsenic trioxide in U87 human glioblastoma cells

Pucer¹,

Castino²,

Mirković³

et al. 2010

Biological Chemistry

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Arsenic trioxide (arsenite) was the first chemotherapeutic drug to be described and is now being rediscovered in cancer treatment, including glioblastoma multiforme. Arsenite toxicity triggers autophagy in cancer cells, although final stages of the process involve executive caspases, suggesting an interplay between autophagic and apoptotic pathways that awaits to be explained at a molecular level. We evaluated the contribution of the lysosomal cathepsins (Cat) L and B, which are upregulated in glioblastomas, in the mechanism of arsenite toxicity in human glioblastoma cells. Arsenite treatment induced autophagosome formation and permeabilization of mitochondria, followed by caspase 3/7-mediated apoptosis. The autophagy inhibitor 3-methyladenine protected from arsenite toxicity, whereas bafilomycin A1 did not. Furthermore, arsenite significantly decreased CatB levels and selectively inhibited its cellular and recombinant protein activity, while not affecting CatL. However, downregulation of CatL greatly enhanced apoptosis by arsenite. Our results show that arsenite toxicity involves a complex interplay between autophagy and apoptosis in human glioblastoma cells and is associated with inhibition of CatB, and that this toxicity is highly exacerbated by simultaneous CatL inhibition. The latter points to a synergy that could be used in clinical treatment to lower the therapeutic dose, thus avoiding the toxic side effects of arsenite in glioblastoma management.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 96%

Differential role of cathepsins B and L in autophagy-associated cell death induced by arsenic trioxide in U87 human glioblastoma cells

Pucer¹,

Castino²,

Mirković³

et al. 2010

Biological Chemistry

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“…Among various types of invasive mechanisms (13) tively, changed expression of Kiaa1199, SerpinB2, and EphB2 in cocultured U87-MG cells implies a possible the mesenchymal type of invasion, which is associated with GBM, relies on ECM matrix degradation where hMSC role in the initiation of U87-MG senescence. proteolytic enzymes play a major role (28,30,50). Yet, hMSCs.…”

Section: Cellular Cross-talk Has Impact On Cell Fitnessmentioning

confidence: 99%

Human Mesenchymal Stem Cells Exploit the Immune Response Mediating Chemokines to Impact the Phenotype of Glioblastoma

et al. 2012

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In contrast to the application of human mesenchymal stem cells (hMSCs) in regenerative medicine, only a limited number of studies are addressing their use in anticancer therapy. As the latter may represent a new hope to improve the survival of patients with glioblastoma multiformae (GBM), the most common and malignant form of the brain tumors, we aimed to investigate the interactions of hMSCs and GBM cells under in vitro conditions. Four hMSC clones and three different GBM cell lines were used to study their mutual paracrine interactions in cocultures compared to their monocultures, where cells were grown under the same experimental conditions. The effects on cell growth, proliferation, and invasion in Matrigel were quantified. Further, bioinformatics tools were used to relate these results to the data obtained from cytokine macroarrays and cDNA microarrays that revealed proteins and genes significantly involved in cellular crosstalk. We showed that hMSCs are responsible for the impairment of GBM cell invasion and growth, possibly via induction of their senescence. On the other hand, GBM cells inversely affected some of these characteristics in hMSCs. We found CCL2/MCP-1 to be the most significantly regulated chemokine during hMSC and U87-MG paracrine signaling in addition to several chemokines that may account for changed cocultured cells' phenotype by affecting genes associated with proliferation (Pmepa-1, NF-κB, invasion (EphB2, Sod2, Pcdh18, Col7A1, Gja1, Mmp1/2), and senescence (Kiaa1199, SerpinB2). As we functionally confirmed the role of CCL2/MCP-1 in GBM cell invasion we thereby propose a novel mechanism of CCL2/ MCP-1 antimigratory effects on GBM cells, distinct from its immunomodulatory role. Significant alterations of GBM phenotype in the presence of hMSCs should encourage the studies on the naive hMSC use for GBM treatment.

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“…In general, decreased levels of cystatins, combined with elevated levels of cysteine cathepsins (an imbalance between proteolytic enzymes and their inhibitors), is suggested to be the mechanism of action of cathepsins in cancer progression 16, 19. This has also been verified in gliomas 9, 17, 18.…”

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confidence: 95%

The regulation of cysteine cathepsins and cystatins in human gliomas

Gole

Huszthy

Popović³

et al. 2012

Intl Journal of Cancer

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Cysteine cathepsins play an important role in shaping the highly infiltrative growth pattern of human gliomas. We have previously demonstrated that the activity of cysteine cathepsins is elevated in invasive glioblastoma (GBM) cells in vitro, in part due to attenuation of their endogenous inhibitors, the cystatins. To investigate this relationship in vivo, we established U87-MG xenografts in non-obese diabetic (NOD)/severe combined immunodeficiency (SCID)-enhanced green fluorescent protein (eGFP) mice. Here, tumor growth correlated with an elevated enzymatic activity of CatB both in the tumor core and at the periphery, whereas CatS and CatL levels were higher at the xenograft edge compared to the core. Reversely, StefB expression was detected in the tumor core, but it was generally absent in the tumor periphery, suggesting that downregulation of this inhibitor correlates with in vivo invasion. In human GBM samples, all cathepsins were elevated at the tumor periphery compared to brain parenchyma. CatB was also typically associated with angiogenic endothelia and necrotic areas. StefB was mainly detected in the tumor core, whereas CysC and StefA were evenly distributed, reflecting the observations in the xenografts. However, at the mRNA level, no differences in cathepsins and cystatins were observed between the tumor center and the periphery in both human biopsies and xenografts. Interestingly, in human tumors, cathepsin and stefin transcript levels correlated with CD68 and CXCR4 levels, but not with epidermal growth factor receptor (EGFR). Moreover, we reveal for the first time that an elevated StefA mRNA level is a highly significant prognostic factor for patient survival.

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Cysteine Cathepsins and Cystatins as Cancer Biomarkers

Cited by 12 publications

References 111 publications

Differential role of cathepsins B and L in autophagy-associated cell death induced by arsenic trioxide in U87 human glioblastoma cells

Differential role of cathepsins B and L in autophagy-associated cell death induced by arsenic trioxide in U87 human glioblastoma cells

Human Mesenchymal Stem Cells Exploit the Immune Response Mediating Chemokines to Impact the Phenotype of Glioblastoma

The regulation of cysteine cathepsins and cystatins in human gliomas

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