Invasiveness of Transformed Human Breast Epithelial Cell Lines Is Related to Cathepsin B and Inhibited by Cysteine Proteinase Inhibitors

Bervar, Aleš; Zajc, Irena; Sever, Natasa; Katunuma, Nobuhiko; Sloane, Bonnie F.; Lah, Tamara T.

doi:10.1515/bc.2003.050

Cited by 63 publications

(36 citation statements)

References 22 publications

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“…The antiangiogenic effects of pCU are also in agreement with previous studies showing that inhibition of uPAR activity suppressed retinal neovascularization, possibly through a reduction in cell-associated proteolytic activity, cell signaling or cell-matrix adhesion necessary for cell migration during angiogenesis (McGuire et al, 2003). Synthetic cysteine proteinase inhibitors, selective for cathepsin B, have been shown to significantly reduce the invasiveness of MCF10AT cells (Bervar et al, 2003). Several studies using selective inhibitors of uPA or small, synthetic cyclic, competitive uPA antagonists derived from the binding sites of uPAR resulted in highly significant reduction of tumor burden (Evans et al, 1998;Sato et al, 2002).…”

Section: Cathepsin B and Upar Sirna Suppresses Intracranial Tumor Growthsupporting

confidence: 89%

“…Cathepsin B was shown to activate precursors of serine proteinases to their active forms, such as pro-uPA (Kobayashi et al, 1991) and metalloproteinases, such as pro-stromelysin (Murphy et al, 1992). Invasiveness through Matrigel of transformed human breast epithelial cell lines was related to cathepsin B expression and was inhibited by cysteine proteinase inhibitors (Bervar et al, 2003). In ovarian cancer cells, inhibition of cell surface cathepsin B prevents activation of pro-uPA, and subsequently, invasion of the carcinoma cells through Matrigel (Kobayashi et al, 1993).…”

Section: Cathepsin B and Upar Sirna Suppresses Intracranial Tumor Growthmentioning

confidence: 99%

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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: 89%

Section: Cathepsin B and Upar Sirna Suppresses Intracranial Tumor Growthmentioning

confidence: 99%

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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“…Intracellular and extracellular cathepsin B activity contributes to the in vitro invasiveness of MCF10AT cells (Premzl et al, 2003). Synthetic cysteine proteinase inhibitors, selective for cathepsin B, have been shown to significantly reduce the invasiveness of MCF10AT cells (Bervar et al, 2003). Increased cathepsin B activity was observed in the invasive tumor regions of human colon cancer samples (Emmert-Buck et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis

et al. 2004

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Extracellular proteases have been shown to cooperatively influence matrix degradation and tumor cell invasion through proteolytic cascades, with individual proteases having distinct roles in tumor growth, invasion, migration and angiogenesis. Matrix metalloproteases (MMP)-9 and cathepsin B have been shown to participate in the processes of tumor growth, vascularization and invasion of gliomas. In the present study, we used a cytomegalovirus promoter-driven DNA template approach to induce hairpin RNA (hpRNA)-triggered RNA interference (RNAi) to block MMP-9 and cathepsin B gene expression with a single construct. Transfection of a plasmid vectorexpressing double-stranded RNA (dsRNA) for MMP-9 and cathepsin B significantly inhibited MMP-9 and cathepsin B expression and reduced the invasive behavior of SNB19, glioblastoma cell line in Matrigel and spheroid invasion models. Downregulation of MMP-9 and cathepsin B using RNAi in SNB19 cells reduced cell-cell interaction of human microvascular endothelial cells, resulting in the disruption of capillary network formation in both in vitro and in vivo models. Direct intratumoral injections of plasmid DNA expressing hpRNA for MMP-9 and cathepsin B significantly inhibited established glioma tumor growth and invasion in intracranial tumors in vivo. Further intraperitoneal (ip) injections of plasmid DNA expressing hpRNA for MMP-9 and cathepsin B completely regressed pre-established tumors for a long time (4 months) without any indication of these tumor cells. For the first time, these observations demonstrate that the simultaneous RNAi-mediated targeting of MMP-9 and cathepsin B has potential application for the treatment of human gliomas.

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“…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). In malignancies including glioma, meningioma, prostate cancer and oral cancer, RNA interference was used to down-regulate tumor-related genes including cathepsin B, and the results showed significantly inhibited invasion and metastasis (13,14,21,28).…”

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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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Invasiveness of Transformed Human Breast Epithelial Cell Lines Is Related to Cathepsin B and Inhibited by Cysteine Proteinase Inhibitors

Cited by 63 publications

References 22 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

Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis

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

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