Cathepsin B and its inhibitor stefin A in brain tumors

Strojnik, Tadej; Zajc, Irena; Bervar, Aleš; Židanik, Boris; Golouh, Rastko; Kos, Janko; Dolenc, Vinko V.; Lah, Tamara T.

doi:10.1007/bf03376544

Cited by 28 publications

(34 citation statements)

References 3 publications

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“…Our research and that of others have previously demonstrated that cathepsin B and uPAR levels are overexpressed during the progression of glioma tumor growth (Rempel et al, 1994), (Yamamoto et al, 1994;Gladson et al, 1995;Sivaparvathi et al, 1995;Strojnik et al, 1999). Our previous work demonstrated that antisense stable clones of SNB19 for cathepsin B (Mohanam et al, 2002) and uPAR Mohanam et al, 1997) were less invasive in vitro and formed very small tumors in vivo.…”

Section: Cathepsin B and Upar Sirna Suppresses Intracranial Tumor Growthsupporting

confidence: 67%

RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas

et al. 2004

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RNA interference (RNAi) provides a powerful method for gene silencing in eukaryotic cells, including proliferating mammalian cells. Here, we determined whether RNAi could be utilized to inhibit the expression of proteases implicated in the extracellular matrix degradation, which is characteristic of tumor progression. We have previously shown that antisense stable clones of uPAR and cathepsin B were less invasive and did not form tumors when injected intracranially ex vivo. Since antisense-mediated gene silencing does not completely inhibit the translation of target mRNA and high molar concentrations of antisense molecules are required to achieve gene silencing, we used the RNAi approach to silence uPAR and cathepsin B in this study. We found that the expression of doublestranded RNA leads to the efficient and specific inhibition of endogenous uPAR and cathepsin B protein expression in glioma cell lines as determined by Western blotting. We also found the RNAi of uPAR and cathepsin B reduces glioma cell invasion and angiogenesis in in vitro and in vivo models. Intratumoral injections of plasmid vectors expressing hpRNA for uPAR and cathepsin B resulted in the regression of pre-established intracranial tumors. Further, RNAi for uPAR and cathepsin B inhibited cell proliferation and reduced the levels of pERK and pFAK compared to controls. Taken together, our findings indicate for the first time that RNAi operates in human glioma cells with potential application for cancer gene therapy.

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Section: Cathepsin B and Upar Sirna Suppresses Intracranial Tumor Growthsupporting

confidence: 67%

RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas

et al. 2004

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“…High cathepsin B expression has been noted in (10,(20)(21)(22)(23)(24). Recent studies have shown that small molecule inhibitors of recombinant proteases (stefin A/B, AC-LVK-CHO) and a specific cathepsin B inhibitor (CA-074) can suppress the metastasis of ovarian and breast cancers (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…In prostate, breast, lung, colorectal, head and neck, uterine and metastatic ovarian cancers, it has been reported that the imbalance between cathepsins and their inhibitors may result in metastasis and invasion. As such, the expression and/or activity of cathepsins and their inhibitors may be used as indicators for evaluating survival rates and recurrence risks (10,(20)(21)(22)(23)(24). Recent studies have shown that small molecule inhibitors of recombinant proteases (stefin A/B, AC-LVK-CHO) and a specific cathepsin B inhibitor (CA-074) can suppress the metastasis of ovarian and breast cancers (25)(26)(27).…”

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confidence: 99%

Expression and clinical significance of cathepsin B and stefin A in laryngeal cancer

Chen²,

Wang³

et al. 2011

Oncol Rep

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Abstract. The aim of this study was to investigate the roles of the cathepsin B cysteine protease and its endogenous inhibitor stefin A in laryngeal cancer. Immunohistochemistry was employed to detect the expression of cathepsin B and stefin A in 84 patients with laryngeal cancer, respectively. The protein expression of stefin A was negatively associated with lymphatic metastasis, recurrence of laryngeal cancer and the survival rate, which was not observed with cathepsin B protein expression. Both down-regulation of cathepsin B and up-regulation of stefin A in vitro significantly inhibited the migration, invasion and proliferation of laryngeal cancer cells, respectively. Our results strongly suggest that stefin A may be a potential predictor of laryngeal cancer and may be used in the molecular diagnosis and gene therapy of laryngeal cancer. Cathepsin B may be used as a promising therapeutic target in the treatment of laryngeal cancer. IntroductionLaryngeal cancer is a common head and neck malignancy and accounts for 7% of all malignancies, and the incidence of laryngeal cancer has been increasing over the years. Laryngeal cancer is associated with a high prevalence of local invasion and cervical lymph node metastasis, and a majority of patients die of cervical recurrence and metastasis. Investigations concerning the invasion and metastasis of laryngeal cancer may clarify the exact mechanisms underlying these processes and may identify novel therapeutic targets. The invasion and metastasis of cancers are complex, multistep, multifactor interacting, and dynamic biological processes involving cancer cells, host cells and the extracellular matrix (1). Invasion is a prerequisite of metastasis that depends on adherence and degradation of the extracellular matrix by degradative enzymes (2). Liotta et al proposed that the invasion and metastasis of cancers involve three steps: i) adherence between cancer cells and the extracellular matrix; ii) the release of proteolytic enzymes causing the degradation of the extracellular matrix; and iii) migration of cancer cells under the action of chemokines. This theory suggests that adherence, degradation and migration act sequentially and repetitively, ultimately resulting in sustained invasion and distal metastasis of cancer cells (3). The impairment of the basement membrane has been considered an important marker of cancer invasion, and the degradation of the extracellular matrix by proteolytic enzymes is a critical step of invasion and metastasis of cancer cells. Based on the substrates and pH values for enzyme catalysis, proteolytic enzymes can be classified into four types: serine proteases, matrix metalloproteinases, cysteine proteases, and aspartic proteases. These proteases have different biological functions related to cancer and play an important role in the occurrence, invasion, angiogenesis, and metastasis of cancers. Cancer invasion depends on the local concentration of proteases and the balance between proteases and their inhibitors. Under normal conditions, protease...

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“…We earlier reported high levels of cathepsin B in tumor and endothelial cells of brain tumor tissues (Sivaparvathi et al, 1995). Strojnik et al (1999) demonstrated that cathepsin B is localized in tumor cells, macrophages, and endothelial cells of primary tumors of the CNS and its level of expression is a strong prognostic marker for primary tumors of the CNS. Changes in cathepsin B expression and subcellular localization correlated with increased grade, local invasion, and clinical evidence of invasion (Demchik et al, 1999;Rempel et al, 1994), thereby implicating cathepsin B in both glioma progression and invasion.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of cathepsin B expression impairs the invasive and tumorigenic potential of human glioblastoma cells

et al. 2001

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Increases in abundance of cathepsin B transcript and protein correlate with increases in tumor grade and alterations in subcellular localization and activity of cathepsin B. The enzyme is able to degrade the components of the extracellular matrix (ECM) and activate other proteases capable of degrading ECM. To investigate the role played by this protease in the invasion of brain tumor cells, we transfected SNB19 human glioblastoma cells with a plasmid containing cathepsin B cDNA in antisense orientation. Control cells were transfected with vector alone. Clones expressing antisense cathepsin B cDNA exhibited signi®cant reductions in cathepsin B mRNA, enzyme activity and protein compared to controls. Matrigel Invasion assay showed that the antisense-transfected cells had a markedly diminished invasiveness compared with controls. When tumor spheroids containing antisense transfected SNB19 cells expressing reduced cathepsin B were co-cultured with fetal rat brain aggregates, invasion of fetal rat brain aggregates was signi®cantly reduced. Green Fluorescent Protein (GFP) expressing parental cells and antisense transfectants were generated for detection in mouse brain tissue without any postchemical treatment. Intracerebral injection of SNB19 stable antisense transfectants resulted in reduced tumor formation in nude mice. These results strongly support a role for cathepsin B in the invasiveness of human glioblastoma cells and suggest cathepsin B antisense may prove useful in cancer therapy. Oncogene (2001) 20, 3665 ± 3673.

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Cathepsin B and its inhibitor stefin A in brain tumors

Cited by 28 publications

References 3 publications

RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas

RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas

Expression and clinical significance of cathepsin B and stefin A in laryngeal cancer

Down-regulation of cathepsin B expression impairs the invasive and tumorigenic potential of human glioblastoma cells

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