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

Mohanam, Sanjeeva; Jasti, Sushma L.; Kondraganti, Sudha R.; Chandrasekar, Nirmala; Lakka, Sajani S.; Y, Kin; Fuller, Gregory N.; Yung, Alfred; Kyritsis, Anthanassios P.; Dinh, Dzung H.; Olivero, William C.; Gujrati, Meena; Ali‐Osman, Francis; Rao, Jasti S.

doi:10.1038/sj.onc.1204480

Cited by 83 publications

(56 citation statements)

References 35 publications

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“…Using the antisense approach, a reduction in the malignancy and/or metastatic potential has also been achieved by inhibition of the urokinase plasminogen activator (Haeckel et al, 1998), matrilysin (Hasegawa et al, 1998), matrix metalloproteinase-9 (Kondraganti et al, 2000), cathepsin-B (Mohanam et al, 2001), and cathepsin-L (Kirschke et al, 2000), whereas antisense inhibition of TIMPs increased tumorigenicity (Khokha et al, 1989;Castagnino et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells

et al. 2002

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Overexpression of cathepsin-D in primary breast cancer has been associated with rapid development of clinical metastasis. To investigate the role of this protease in breast cancer growth and progression to metastasis, we stably transfected a highly metastatic human breast cancer cell line, MDA-MB-231, with a plasmid containing either the full-length cDNA for cathepsin-D or a 535 bp antisense cathepsin-D cDNA fragment. Clones expressing antisense cathepsin-D cDNA that exhibited a 70 -80% reduction in cathepsin-D protein, both intra-and extracellularly compared to controls, were selected for further experiments. These antisense-transfected cells displayed a reduced outgrowth rate when embedded in a Matrigel matrix, formed smaller colonies in soft agar and presented a significantly decreased tumor growth and experimental lung metastasis in nude mice compared with controls. However, manipulating the cathepsin-D level in the antisense cells has no effect on their in vitro invasiveness. These studies demonstrate that cathepsin-D enhances anchorage-independent cell proliferation and subsequently facilitates tumorigenesis and metastasis of breast cancer cells. Our overall results provide the first evidence on the essential role of cathepsin-D in breast cancer, and support the development of a new cathepsin-D-targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells

et al. 2002

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“…Direct evidence of the role of uPA in invasion was reported that downregulation of uPA decreased the invasion of human glioblastoma cells (Mohanam et al, 2001). Tumor invasion involves adhesive and migratory events in addition to the proteolytic degradation of ECM.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

Chandrasekar

Mohanam

Gujrati³

et al. 2003

Oncogene

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The ability of glioma cells to migrate great distances from a primary tumor mass is the primary cause of tumor recurrence. The urokinase-type plasminogen activator (uPA) is a serine protease that can initiate proteolytic cascades, which result in remodeling of extracellular matrix and basement membrane, allowing cells to move across and through these barriers. The binding between uPA and its receptor uPAR also mediates several signaling events that seem to contribute to the evolution of a migratory phenotype. In this study, we determined how the downregulation of uPA affects the signaling pathways leading to cell migration. Stably transfecting human glioblastoma cells with antisense uPA decreased the amount of cell-bound uPA and disrupted actin cytoskeleton formation and cell migration. The phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathway has been suggested to mediate migration in various cancer cells. The antisense-uPA clones also had less phosphorylated PI3k and Akt than control cells, a finding associated with decreased cell migration, G2/M-phase arrest, and decreased clonogenic survival. Decreased activation of PI3k and the antiapoptotic factor Akt was not sufficient to induce apoptosis in the antisense-uPA clones, but staurosporine sensitized them to apoptosis to a greater extent than control cells. These results indicate that PI3k/ Akt pathway is involved in the signaling cascade required to induce cell migration and that uPA has a direct role in regulating migration.

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“…9 Human glioblastoma cell lines also exhibit higher levels of CatB expression than lower grade astrocytomas 10 and the functional relevance of the enzyme is confirmed by a marked reduction in in vitro invasiveness of a glioblastoma cell line transfected with antisense CatB cDNA. 11 There is evidence of altered trafficking of CatB in glioblastomas, with a redistribution of enzyme to the cell periphery. 12 In addition, a potential role in invasion has been suggested by high levels at the tumor periphery and in infiltrating cells.…”

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confidence: 99%

The Clinical Significance of Cathepsin S Expression in Human Astrocytomas

Flannery¹,

Gibson²,

Mirakhur³

et al. 2003

The American Journal of Pathology

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Early local invasion by astrocytoma cells results in tumor recurrence even after apparent total surgical resection, leading to the poor prognosis associated with malignant astrocytomas. Proteolytic enzymes have been implicated in facilitating tumor cell invasion and the current study was designed to characterize the expression of the cysteine proteinase cathepsin S (CatS) in astrocytomas and examine its potential role in invasion. Immunohistochemical analysis of biopsies demonstrated that CatS was expressed in astrocytoma cells but absent from normal astrocytes, oligodendrocytes, neurones and endothelial cells. Microglial cells and macrophages were also positive. Assays of specific activity in 59 astrocytoma biopsies confirmed CatS expression and in addition demonstrated that the highest levels of activity were expressed in grade IV tumors. CatS activity was also present in astrocytoma cells in vitro and the extracellular levels of activity were highest in cultures derived from grade IV tumors. In vitro invasion assays were carried out using the U251MG cell line and the invasion rate was reduced by up to 61% in the presence of the selective CatS inhibitor 4-Morpholineurea-LeuHomoPhe-vinylsulphone. We conclude that CatS expression is up-regulated in astrocytoma cells and provide evidence for a potential role for CatS in invasion. Astrocytomas are the commonest primary brain tumors and within this group the malignant grade III and IV tumors predominate (anaplastic astrocytomas and glioblastomas). Despite their non-metastatic nature, prognosis is poor because tumor infiltration of surrounding brain leads to recurrence even after apparently radical surgery. Multiple stereotactic biopsies of astrocytomas have demonstrated isolated tumor cells at considerable distances from the main tumor mass, 1 and recent investigations 2 have shown that tumor cells may be cultured from histologically normal brain at a distance greater than 4 cm from the gross tumor. Astrocytoma invasion is an active process that involves interactions with the host extracellular matrix (ECM), proteolytic modification of the ECM, and migration of the tumor cells into the modified matrix. 3 Members of the metalloproteinase, serine proteinase, and cysteine proteinase superfamilies have been linked to glioma invasion. 4 The cysteine proteinase cathepsin B (CatB) is expressed in gliomas in vitro 5 and immunohistochemical studies have demonstrated its presence in astrocytomas and glioblastomas in contrast to its absence from astrocytes in normal brain. 6,7 The expression and activity of CatB is higher in anaplastic astrocytomas and glioblastomas compared with low-grade tumors and normal brain 8 and high levels of CatB are positively correlated with poor survival. 9 Human glioblastoma cell lines also exhibit higher levels of CatB expression than lower grade astrocytomas 10 and the functional relevance of the enzyme is confirmed by a marked reduction in in vitro invasiveness of a glioblastoma cell line transfected with antisense CatB cDNA. 11 There is evide...

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

Cited by 83 publications

References 35 publications

Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells

Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells

Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

The Clinical Significance of Cathepsin S Expression in Human Astrocytomas

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