Cathepsin L is involved in cathepsin D processing and regulation of apoptosis in A549 human lung epithelial cells

Wille, Aline; Gerber, Annegret; Heimburg, Anke; Reisenauer, Anita; Peters, Christoph; Säftig, Paul; Reinheckel, Thomas; Welte, Tobias; Bühling, Frank

doi:10.1515/bc.2004.082

Cited by 60 publications

(45 citation statements)

References 22 publications

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“…CTSL is anti-apoptotic regardless of whether the induction of apoptosis triggers the intrinsic or extrinsic pathway, or even an indirect pathway via autophagy, upon treatment with arsenic trioxide (16). By contrast, other authors have highlighted the role of CTSL in conferring resistance towards chemotherapeutics and thus mediating an anti-apoptotic effect (17,18). However, to date, little is known regarding the involvement of CTSL in drug-resistant ovarian carcinoma cells.…”

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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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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“…Indeed, it could result in prevention of cathepsin B maturation, since the trimming of the N-terminal extensions of cathepsin B propeptide is no longer possible (55). Additionally, cathepsin L inhibition could affect cathepsin D processing (14). From all of the above, it is feasible that sialostatin L targets two fundamental enzymes controlling the activation of proteolytic cascades in both the extracellular and intracellular compartments.…”

Section: Discussionmentioning

confidence: 99%

“…Besides their implication in antigen presentation (8) and immune system development (9), they are also involved in epidermal homeostasis (10), neovascularization (11), extracellular matrix degradation and neutrophil chemotaxis during inflammation (12,13), apoptosis (14), and (last but not least) proliferation of malignant cells and their subsequent invasion into healthy tissues during metastasis (15,16).…”

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confidence: 99%

Antiinflammatory and Immunosuppressive Activity of Sialostatin L, a Salivary Cystatin from the Tick Ixodes scapularis

Kotsyfakis

Sá-Nunes

Francischetti

et al. 2006

Journal of Biological Chemistry

193

180

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Here we report the ability of the tick Ixodes scapularis, the main vector of Lyme disease in the United States, to actively and specifically affect the host proteolytic activity in the sites of infestation through the release of a cystatin constituent of its saliva. The cystatin presence in the saliva was verified both biochemically and immunologically. We named the protein sialostatin L because of its inhibitory action against cathepsin L. We also show that the proteases it targets, although limited in number, have a prominent role in the proteolytic cascades that take place in the extracellular and intracellular environment. As a result, sialostatin L displays an antiinflammatory role and inhibits proliferation of cytotoxic T lymphocytes. Beyond unraveling another component accounting for the properties of tick saliva, contributing to feeding success and pathogen transmission, we describe a novel tool for studying the role of papainlike proteases in diverse biologic phenomena and a protein with numerous potential pharmaceutical applications.

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“…They can act as transcriptional activators (63), and there can be cross-talks between cathepsins, where for example cathepsin L is involved in CTSD processing and regulation (64). The CTSD gene is controlled by a mixed promoter that contains features of both housekeeping and regulated genes (65)(66)(67)(68).…”

Section: Discussionmentioning

confidence: 99%

Cathepsin D, a Lysosomal Protease, Regulates ABCA1-mediated Lipid Efflux

Haidar

Kiss

Sarov‐Blat

et al. 2006

Journal of Biological Chemistry

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To identify genes involved in the regulation of plasma high density lipoprotein (HDL) cholesterol (HDL-C) levels, patients with low HDL-C and age-and sex-matched controls (normal HDL-C) were extensively characterized. Comparative transcriptome analysis was carried out in cholesterol-loaded monocytederived macrophages from low HDL subjects segregated into groups with or without cholesterol efflux defects or ABCA1 mutations. Clusters of differentially regulated genes were evident in the low HDL groups as compared with controls. Of particular note, expression of cathepsin D (CTSD), a lysosomal proteinase, was reduced by ϳ50% in monocyte-derived macrophages of low HDL-C subjects, most significantly those with cholesterol efflux defects but without mutations in ABCA1 (p < 0.01). These results were verified by reverse transcription-PCR and replicated in a second cohort. We show here that blocking the activity or expression of CTSD, by pepstatin or CTSD small interfering RNA, respectively, reduced ABCA1 expression and protein abundance in both macrophages and CHO cells and apolipoprotein A-I-mediated lipid efflux by more than 70%. Conversely, expression of CTSD increased both ABCA1 mRNA expression and cellular ABCA1 protein. Consistent with its role in the proteolytic processing of prosaposin, inactivation of CTSD function resulted in the accumulation of glycosphingolipid and free cholesterol in late endosomes/lysosomes, a phenotype similar to NPC1 deficiency. Inhibition of CTSD also caused retention of ABCA1 in lysosomal compartments, reducing its trafficking to the plasma membrane. These studies demonstrate a novel and potentially important role for CTSD in intracellular cholesterol trafficking and ABCA1-mediated efflux. Therefore, decreased CTSD expression may contribute to low plasma HDL-C levels.

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Cathepsin L is involved in cathepsin D processing and regulation of apoptosis in A549 human lung epithelial cells

Cited by 60 publications

References 22 publications

Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy

Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy

Antiinflammatory and Immunosuppressive Activity of Sialostatin L, a Salivary Cystatin from the Tick Ixodes scapularis

Cathepsin D, a Lysosomal Protease, Regulates ABCA1-mediated Lipid Efflux

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