Complexity of cancer protease biology: Cathepsin K expression and function in cancer progression

Verbovšek, Urška; Noorden, C. J. F. Van; Lah, Tamara T.

doi:10.1016/j.semcancer.2015.08.010

Cited by 82 publications

(63 citation statements)

References 173 publications

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“…Herein, the cathepsin B expression correlated with cell invasion, which was inhibited by its selective inhibitor CA-074. Cathepsin B is associated in the invasion process in many types of cancer [6] and these data confirmed the essential role of this cathepsin, in contrast to cathepsin L [47] and cathepsin K [7, 48] in GBM invasion. Interestingly, in the in vivo spheroid invasion assay of established GBM cell lines and primary GBM cultures from patients cathepsin B was highly expressed and only cathepsin B silencing and cathepsin B inhibitor, but not those of cathepsin L and S, inhibited GBM cell invasion in the collagen I embedded spheroids [49].…”

Section: Discussionmentioning

confidence: 63%

Mesenchymal stem cells differentially affect the invasion of distinct glioblastoma cell lines

et al. 2017

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Glioblastoma multiforme are an aggressive form of brain tumors that are characterized by distinct invasion of single glioblastoma cells, which infiltrate the brain parenchyma. This appears to be stimulated by the communication between cancer and stromal cells. Mesenchymal stem cells (MSCs) are part of the glioblastoma microenvironment, and their ‘cross-talk’ with glioblastoma cells is still poorly understood. Here, we examined the effects of bone marrow-derived MSCs on two different established glioblastoma cell lines U87 and U373. We focused on mutual effects of direct MSC/glioblastoma contact on cellular invasion in three-dimensional invasion assays in vitro and in a zebrafish embryo model in vivo. This is the first demonstration of glioblastoma cell-type-specific responses to MSCs in direct glioblastoma co-cultures, where MSCs inhibited the invasion of U87 cells and enhanced the invasion of U373. Inversely, direct cross-talk between MSCs and both of glioblastoma cell lines enhanced MSC motility. MSC-enhanced invasion of U373 cells was assisted by overexpression of proteases cathepsin B, calpain1, uPA/uPAR, MMP-2, -9 and -14, and increased activities of some of these proteases, as determined by the effects of their selective inhibitors on invasion. In contrast, these proteases had no effect on U87 cell invasion under MSC co-culturing. Finally, we identified differentially expressed genes, in U87 and U373 cells that could explain different response of these cell lines to MSCs. In conclusion, we demonstrated that MSC/glioblastoma cross-talk is different in the two glioblastoma cell phenotypes, which contributes to tumor heterogeneity.

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Section: Discussionmentioning

confidence: 63%

Mesenchymal stem cells differentially affect the invasion of distinct glioblastoma cell lines

et al. 2017

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“…Thus, in order to design a powerful and specific Cathepsin inhibitor, it is of fundamental importance to have detailed knowledge of the features of each sub-site of each Cathepsin [37][38][39]. In addition, it is worth highlighting that this class of enzyme is related to several pathological processes such as osteoporosis (Cathepsin K) [40,41], neurodegenerative disease (Cathepsin D) [42] and metastasis in several types of cancer (Cathepsins B, K, L and S) [43][44][45]. Hence, Cathepsins are promising targets for the treatment of such disorders [46].…”

Section: Decane (1) (3e)-2-chloro-3-(chloromethylidene)-2-(4-methoxymentioning

confidence: 99%

Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

Caracelli

Maganhi

Cardoso

et al. 2017

Zeitschrift Für Kristallographie - Crystalline Materials

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Abstract. The molecular structures of the halotelluroxetanes pMeOC6H4Te(X)[C(=C(H)Xꞌ)C(CH2)nO], X = Xꞌ = Cl and n = 6 (1) and X = Cl, Xꞌ = Br and n = 5 (4), show similar binuclear aggregates sustained by { … Te-O}2 cores comprising covalent Te-O and secondary Te⋯O interactions. The resulting C2ClO2(lone-pair) sets define pseudo-octahedral geometries. In each structure, C-X⋯(arene) interactions lead to supramolecular layers. Literature studies have shown these and related compounds (i.e. 2: X = Xꞌ = Cl and n = 5; 3: X = Xꞌ = Br and n = 5) to inhibit Cathepsins B, K, L and S to varying extents. Molecular docking calculations have been conducted on ligands (i.e. cations derived by removal of the telluriumbound X atoms) 1ꞌ-3ꞌ (note 3ꞌ = 4ꞌ) enabling correlations between affinity for sub-sites and inhibition. The common feature of all docked complexes was the formation of a Te-S covalent bond with cysteine residues, the relative stability of the ligands with an E-configuration and the formation of a C-O … π interaction with the phenyl ring; for 1ꞌ the Te-S covalent bond was weak, a result correlating with its low inhibition profile. At the next level differences are apparent, especially with respect to the interactions formed by the organic-ligand-bound halides.

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“…[115] CatK is also considered a suitable drug target for certain bone cancers where excessive bone resorption/destruction is a hallmark. [177] …”

Section: Expert Opinionmentioning

confidence: 99%

Cathepsin K osteoporosis trials, pycnodysostosis and mouse deficiency models: Commonalities and differences

Brὂmme

Panwar

Turan

2016

Expert Opinion on Drug Discovery

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Several selective cathepsin K inhibitors have been developed and evaluated in preclinical and clinical studies. Although all compounds were effective in reducing bone resorption markers, the development of some compounds was terminated either due to side effects or market competition. The most advanced compound is odanacatib, which significantly reduced bone fracture rates in a 5-year trial but still exhibits safety concerns. The analysis of mouse and human catK deficiencies sheds some light on the consequences of a cathepsin K inhibitor treatment. How predictive the knockout phenotypes are regarding long-term cathepsin K treatment remains unclear. Clearly, more studies are needed to understand the mechanism of the observed side effects and novel approaches are needed to make CatK inhibitors either osteoclast-specific or selective for the inhibition of the collagen matrix without affecting the other activities of the protease.

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Complexity of cancer protease biology: Cathepsin K expression and function in cancer progression

Cited by 82 publications

References 173 publications

Mesenchymal stem cells differentially affect the invasion of distinct glioblastoma cell lines

Mesenchymal stem cells differentially affect the invasion of distinct glioblastoma cell lines

Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

Cathepsin K osteoporosis trials, pycnodysostosis and mouse deficiency models: Commonalities and differences

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