Selective suppression of cathepsin L by antisense cDNA impairs human brain tumor cell invasion in vitro and promotes apoptosis

Levičar, Nataša; Dewey, Ricardo Alfredo; Daley, Emma; Bates, Timothy E.; Davies, Derek; Kos, Janko; Pilkington, Geoffrey J.; Lah, Tamara T.

doi:10.1038/sj.cgt.7700546

Cited by 96 publications

(62 citation statements)

References 38 publications

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“…These movements require disassembly of podocyte cell-cell contacts, an event that by itself may cause or augment proteinuria. Our results in podocytes establish similarities with tumor metastasis in which cathepsin L is involved in tissue invasion and disease progression (40). The functional significance of cathepsin L in podocyte pathobiology is underscored by the finding that cat L Ϫ/Ϫ podocytes are protected from cell detachment and cell-cell junction disassembly.…”

Section: Down-regulation Of ␣ 3 Integrin Protects Against Pan-inducedsupporting

confidence: 68%

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

Reiser¹,

Oh²,

Shirato³

et al. 2004

Journal of Biological Chemistry

158

132

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Podocyte foot process effacement and disruption of the slit diaphragm are typically associated with glomerular proteinuria and can be induced in rats by the injection of puromycin aminonucleoside. Here, we show that the induction of puromycin aminonucleoside nephrosis involves podocyte migration conducted by a coordinated interplay between the cysteine protease cathepsin L and ␣ 3 integrin. Puromycin aminonucleoside treatment up-regulates cathepsin L expression in podocytes in vivo as well as expression and enzymatic activity of cathepsin L in podocytes in vitro. Isolated podocytes from mice lacking cathepsin L are protected from cell puromycin aminonucleoside-induced cell detachment. The functional significance of cathepsin L expression was underscored by the observation that puromycin aminonucleoside-induced cell migration was slowed down in cathepsin L-deficient podocytes and by the preservation of cell-cell contacts and expression of vital slit diaphragm protein CD2AP. Cathepsin L expression and activity were induced in podocytes lacking ␣ 3 integrin. Similarly, acute functional inhibition of ␣ 3 integrin in wild type podocytes with a blocking antibody increased the expression of cathepsin L activity. Downregulation of ␣ 3 integrin protected against puromycin aminonucleoside-induced podocyte detachment. In summary, these data establish that podocyte foot process effacement is a migratory event involving a novel interplay between cathepsin L and ␣ 3 integrin.Glomerular podocytes serve as a final barrier to urinary protein loss by the formation and maintenance of podocyte foot processes and the interposed slit diaphragm (SD) 1 All forms of nephrotic syndrome are characterized by podocyte foot process (FP) effacement and/or molecular reorganization of the slit diaphragm (1). FP effacement requires a precise interplay of multiple cellular functions including structural alterations of the cytoskeleton, movement of FP over the basement membrane, and reconstruction of the slit diaphragm (1). The discovery of several novel podocyte proteins and their mutation analysis including nephrin (2), CD2AP (3), ␣-actinin-4 (4), podocin (5), neph1 (6), and FAT (7) have shed light on the pathogenesis of FP effacement and proteinuria and emphasized the critical role of podocyte FP and the SD in maintaining the function of the glomerular filtration barrier.

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Section: Down-regulation Of ␣ 3 Integrin Protects Against Pan-inducedsupporting

confidence: 68%

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

Reiser¹,

Oh²,

Shirato³

et al. 2004

Journal of Biological Chemistry

158

132

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“…The present findings of reduced tumorigenic potential in cells with decreased CathL production are consistent with these reports but suggest an additional, indirect mechanism by which CathL expression levels may regulate tumorigenicity and metastasis, namely, through control of the IGF-I axis. This function may also account for the reported observations that reduced CathL expression led not only to decreased invasion but also to enhanced apoptosis in glioma and melanoma models (Levicar et al, 2003;Rousselet et al, 2004). A role for CathL in the recycling of EGF has recently been identified in keratinocytes, but in contrast to our own findings, increased EGF recycling was observed in cells deficient in CathL expression (Reinheckel et al, 2005), possibly because of a compensatory overexpression of other cathepsins in these cells.…”

Section: Apoptotic Cells (Fold Increase)contrasting

confidence: 55%

“…The increased expression and altered trafficking of the lysosomal CathL have been extensively documented in various tumor cells and the enzyme has been implicated in tumor migration, invasion and angiogenesis in studies that employed specific inhibitors such as antisense oligonucleotides, antisense RNA and single-chain antiCathL antibodies (Navab et al, 1997;Kirschke et al, 2000;Krueger et al, 2001;Levicar et al, 2003;Rousselet et al, 2004;Yang and Cox, 2007). In these studies, the proinvasive and protumorigenic properties of CathL have generally been attributed to its involvement in ECM degradation, either directly or through participation in proteolytic cascades that lead to the activation of other ECM-degrading proteinases, such as metalloproteinases (Krueger et al, 2001;Levicar et al, 2003). A role for CathL in E-cadherin cleavage has also been identified recently in an animal model of pancreatic cancer (Gocheva et al, 2006).…”

Section: Apoptotic Cells (Fold Increase)mentioning

confidence: 99%

Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels

et al. 2008

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The lysosomal cysteine proteinase cathepsin L is involved in proteolytic processing of internalized proteins. In transformed cells, where it is frequently overexpressed, its intracellular localization and functions can be altered. Previously, we reported that treatment of highly metastatic, murine carcinoma H-59 cells with small molecule cysteine proteinase inhibitors altered the responsiveness of the type I insulin-like growth factor (IGF-I) receptor and consequently reduced cell invasion and metastasis. To assess more specifically the role of cathepsin L in IGF-I-induced signaling and tumorigenicity, we generated H-59 subclones with reduced cathepsin L expression levels. These clonal lines showed an altered responsiveness to IGF-I in vitro, as evidenced by (i) loss of IGF-I-induced receptor phosphorylation and Shc recruitment, (ii) reduced IGF-I (but not IGF-II)-induced cellular proliferation and migration, (iii) decreased anchorage-independent growth and (iv) reduced plasma membrane levels of IGF-IR. These changes resulted in increased apoptosis in vivo and an impaired ability of the cells to form liver metastases. The results demonstrate that cathepsin L expression levels regulate cell responsiveness to IGF-I and thereby identify a novel function for cathepsin L in the control of the tumorigenic/metastatic phenotype.

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“…In addition, CTSL silencing may inhibit the induction of the intrinsic apoptotic pathway in cancer cells via reduced CTSL nuclear activity, involving indirect p53 regulation of caspase 3/7 expression (19). CTSL was shown to be a critical molecule in paclitaxel resistance, however, the mechanism remained unclear.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy

Zhang

Wei

et al. 2016

Oncology Letters

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Abstract. Ovarian cancer is a leading gynecological malignancy associated with high mortality. The development of acquired drug resistance is the primary cause of chemotherapy failure in the treatment of ovarian cancer. To examine the mechanism underlying paclitaxel resistance in ovarian cancer and attempt to reverse it, the present study induced a TAX-resistant ovarian cancer cell line, SKOV3/TAX. Cathepsin L (CTSL) has been found to be overexpressed in ovarian cancer. The aim of the present study was to investigate the possible involvement of CTSL in the development of TAX resistance in ovarian cancer. CTSL expression was knocked down in SKOV3 ovarian cancer cells and their phenotypic changes were analyzed. The effects of silenced CTSL on the resistant cell line were investigated by proliferation and apoptosis analysis compared with control SKOV3 cells. CTSL was more highly expressed in SKOV3/TAX cells compared with SKOV3 cells. Paclitaxel treatment downregulated the expression of CTSL in SKOV-3 but not in the paclitaxel-resistant SKOV3/TAX cells. CTSL small hairpin RNA (shRNA) knockdown significantly potentiated apoptosis induced by paclitaxel compared with SKOV3/TAX cells transfected with control shRNA, suggesting that CTSL contributes to paclitaxel resistance in ovarian cancer cells and that CTSL silencing can enhance paclitaxel-mediated cell apoptosis. Thus, CTSL should be explored as a candidate of therapeutic target for modulating paclitaxel sensitivity in ovarian cancer. IntroductionOvarian cancer is the leading cause of gynecologic cancer-related mortality worldwide, as the majority of patients present with advanced disease at diagnosis (1). The standard treatment for ovarian cancer is surgical cytoreduction and systemic chemotherapy, typically paclitaxel and platinum (2). Although improvement in median survival has been observed in recent decades, the majority of patients eventually succumb to recurrent, progressive disease due to resistance to chemotherapy (3). A combination of paclitaxel and carboplatin has widely been used as the first-line chemotherapy for patients with ovarian cancer. Paclitaxel acts specifically during the G2-M phase of the cell cycle by inducing abnormal spindles and disruption of microtubule dynamics, thereby blocking cell cycle progression. Despite its initial effectiveness as a cancer therapeutic agent, in the majority cases patients eventually become insensitive to paclitaxel-based chemotherapy and relapse (4). With the increasing emergence of paclitaxel resistance, the identification of suitable biomarkers for predicting chemosensitivity to paclitaxel may be key for improving the therapeutic outcome of patients with ovarian cancer.Cathepsin L (CTSL), a lysosomal endopeptidase expressed in most eukaryotic cells, is a member of the papain-like family of cysteine proteinases (5). CTSL has a major role in antigen processing, tumor invasion and metastasis, bone resorption, and turnover of intracellular and secreted proteins involved in growth regulation (6). Increased CTSL leve...

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Selective suppression of cathepsin L by antisense cDNA impairs human brain tumor cell invasion in vitro and promotes apoptosis

Cited by 96 publications

References 38 publications

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

Podocyte Migration during Nephrotic Syndrome Requires a Coordinated Interplay between Cathepsin L and α3 Integrin

Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels

Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy

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