Cathepsin S expression: An independent prognostic factor in glioblastoma tumours—a pilot study

Flannery, Thomas; McQuaid, Stephen; McGoohan, Caroline; McConnell, Robert; McGregor, G.; Mirakhur, M.; Hamilton, Peter; Diamond, James J.; Cran, G. W.; Walker, Brian; Scott, Christopher J.; Martin, S. Lorraine; Ellison, David H.; Patel, Chirag; Nicholson, Clare; Mendelow, David; McCormick, D.; Johnston, Patrick G.

doi:10.1002/ijc.21911

Cited by 77 publications

(62 citation statements)

References 23 publications

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“…Aberrant cathepsin S expression was shown to be significantly greater in astrocytoma and prostate carcinoma sections in comparison with normal tissues (18,35,36), whereas cathepsin L overexpression has been identified in a wide range of human malignancies including melanomas, meningiomas, and colorectal carcinomas (37 -39). Cathepsin K overexpression has been associated with invasive lung adenocarcinomas (40) and breast carcinomas (41) and also identified as the principal protease in giant cell tumor of the bone (42).…”

Section: Discussionmentioning

confidence: 99%

Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L–like proteases in tumor microenvironment

Burden¹,

Snoddy

Buick

et al. 2008

Molecular Cancer Therapeutics

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Human cathepsin L along with cathepsin S, K, and V are collectively known as cathepsin L -like proteases due to their high homology. The overexpression and aberrant activity of each of these proteases has been implicated in tumorigenesis. These proteases contain propeptide domains that can potently inhibit both their cognate protease and other proteases within the cathepsin L -like subfamily. In this investigation, we have produced the cathepsin S propeptide recombinantly and have shown that it is a potent inhibitor of the peptidolytic, elastinolytic, and gelatinolytic activities of the cathepsin L -like proteases. In addition, we show that this peptide is capable of significantly attenuating tumor cell invasion in a panel of human cancer cell lines. Furthermore, fusion of an IgG Fc-domain to the COOH terminus of the propeptide resulted in a chimeric protein with significantly enhanced ability to block tumor cell invasion. This Fc fusion protein exhibited enhanced stability in cell-based assays in comparison with the unmodified propeptide species. This approach for the combined inhibition of the cathepsin L -like proteases may prove useful for the further study in cancer and other conditions where their aberrant activity has been implicated. Furthermore, this strategy for simultaneous inhibition of multiple cysteine cathepsins may represent the basis for novel therapeutics to attenuate tumorigenesis. [Mol Cancer Ther 2008;7(3):538 -47]

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Section: Discussionmentioning

confidence: 99%

Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L–like proteases in tumor microenvironment

Burden¹,

Snoddy

Buick

et al. 2008

Molecular Cancer Therapeutics

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“…Cat S is expressed in astrocytoma derived from brain tumor cell cultures, but not in those cells from normal astrocytes, oligodendrocytes, neurons and endothelial cells 9 . The highest levels of Cat S activity were also found in grade IV tumors among 59 astrocytoma biopsies 10 . In murine model of hepatocellular carcinoma, Cat S was the major overexpressed protease during vessel spouting 11 .…”

Section: Introductionmentioning

confidence: 88%

Effects of novel human cathepsin S inhibitors on cell migration in human cancer cells

Tsai

Lee

Chang

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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Elevated cathepsin S (Cat S) level is correlated with higher migration ability in tumor cells. This study investigates the inhibitory effect of novel synthetic a-ketoamide compounds on cathepsin activity and cancer cell migration. The effect of several a-ketoamide compounds on the activity of recombinant cathepsins (Cat S, Cat L and Cat K) was examined. Two highly metastatic cancer cell lines were incubated with three Cat S-specific compounds (6n, 6w and 6r) to analyze their effect on cellular Cat S activity and cell migration. At a 100 nM concentration, compounds 6n, 6r and 6w effectively inhibited Cat S activity. Cat S activity and cell migration were significantly reduced in CL1-3 cells after treatment with either 6n or 6w at 5 mM. Similar results were also obtained when A2058 cells were treated with 6n. These results highlight the therapeutic potential of a-ketoamide compounds, especially 6n and 6w, to prevent or delay cancer metastasis.

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“…In addition, proteins involved in programmed necrosis, such as Bcl2L12 or cathepsins, are overexpressed in GBM 6,68,69 suggesting that necrogenesis may represent a putative oncogenic mechanism. This hypothesis is supported by several studies assessing the roles of cytosolic proteins with potent oncogenic activities that are released during necrotic death into the extracellular matrix, most notably high-mobility group box 1 (HMGB1/amphotherin) 70 and hepatoma-derived growth factor (HDGF).…”

Section: The Two Faces Of Necrosis-a Benefical Adaptive Warning Systementioning

confidence: 99%

What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator

Stegh¹,

Chin²,

Louis³

et al. 2008

Cell Cycle

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Glioblastoma (GBM) is the most common type of primary brain cancer and carries a dismal prognosis primarily due to the emergence of resistance towards extant radiation, conventional and targeted chemotherapies. Although GBM resists therapy-induced apoptosis, tumors show a seemingly paradoxical propensity for florid intratumoral necrogenesis. This necrosis manifests pathologically as microscopic foci or confluent expanses of necrotic tumor. While it is now well recognized that necrosis is an active cell death process and that apoptosis and necrosis death modalities are intertwined on multiple levels, the precise molecular mechanisms and genetic elements underlying these forms of cell death in GBM remain areas of active investigation. In recent oncogenomic studies, we identified a novel GBM oncoprotein, Bcl2-Like 12 (Bcl2L12), which is significantly expressed in the majority of primary GBM tumor specimens and distantly related to canonical Bcl-2 proteins. Due to its distinctive impact on cell death signaling, Bcl2L12 phenocopies pro-necrotic and anti-apoptotic propensities of highgrade glioma: Mechanistically, we determined that unlike prototypic Bcl-2 family members, Bcl2L12 does not safeguard mitochondrial membrane integrity, but instead potently inhibits apoptosis at the level of post-mitochondrial effector caspase-3/7 activation. A combination of enforced expression, RNAi-mediated extinction, co-localization and protein interaction studies revealed that Bcl2L12 inhibits caspases 3 and 7 via distinct mechanisms. Direct physical interaction underlies Bcl2L12's inhibition of caspase-7 processing, whereas Bcl2L12-induced transcriptional upregulation of the small heat shock protein αB-crystallin is instrumental to neutralization of caspase-3 activation. Mirroring the cellular phenotype elicited by energy depletion, genetic or pharmacologic inhibition of post-mitochondrial apoptosis signaling molecules, Bcl2L12 promotes necrogenesis in glial cells in the context of a proapoptotic stimulus establishing that it represents a novel regulator of the balance between apoptosis and necrosis in GBM.

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Cathepsin S expression: An independent prognostic factor in glioblastoma tumours—a pilot study

Cited by 77 publications

References 23 publications

Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L–like proteases in tumor microenvironment

Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L–like proteases in tumor microenvironment

Effects of novel human cathepsin S inhibitors on cell migration in human cancer cells

What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator

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