Cathepsin L inhibition suppresses drug resistance in vitro and in vivo: a putative mechanism

Zheng, Xin; Chu, Frances; Chou, Pauline M.; Gallati, Christine; Dier, Usawadee; Mirkin, Bernard L.; Mousa, Shaker A.; Rebbaa, Abdelhadi

doi:10.1152/ajpcell.00082.2008

Cited by 53 publications

(48 citation statements)

References 34 publications

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“…The expression of CD27 was even increased after p53 inhibition. Interestingly, CatL inhibition also increased the expression of androgen and estrogen receptors [34], both stimulated by p53 [35,36]. In contrast, in leukemia and lymphoma cells, CatL inhibition stimulated p53-independent apoptosis [37].…”

Section: Discussionmentioning

confidence: 96%

“…CatL inhibition strongly increases the sensitivity of GBM cells to the induction of cell death by arsenic trioxide [21], which is already in a clinical trial to treat malignant glioma (www.clinicaltrials.gov). Drug targets topoisomerase IIa, estrogen receptor, Bcr-Abl, and histone deacetylase have also been shown to accumulate after CatL inhibition, and cells with less CatL activity were consequently less resistant to their corresponding chemotherapeutics [34]. For the application of CatL inhibitors in glioblastoma therapy it would be extremely important to consider that its mechanism may be p53 dependent, as it is known that p53 mutation is one of the most common mutations in cancer.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7

et al. 2011

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Despite all the progress in cancer treatment, glioblastoma, the most malignant tumor of the central nervous system, remains a terminal disease and new therapeutic approaches are urgently needed. A combination of chemotherapy with modifications that lower the apoptotic threshold of cancer cells could be effective. Cathepsin L inhibition was suggested as one of such modifications but the mechanism of cathepsin L anti-apoptotic activity is largely unknown. In the present study we show that, in U87 glioblastoma cells, cathepsin L is present in the nucleus and regulates the transcription of effector caspases 3 and 7. In cells with low cathepsin L expression, p53 and prohibitin--transcription factors that regulate caspase 7 expression--accumulate in the nuclei. The importance of p53 in this process is highlighted by the fact that in U87 cells with inhibited p53 transcriptional activity or in p53-negative cells U251, cathepsin L inhibition did not influence caspase 7 expression and had minimal effect on the level of apoptosis. Since p53 pathways are often mutated in glioblastoma, the findings of our study need to be considered before using cathepsin L inhibition for glioblastoma therapy and suggest that such adjuvant therapy may be effective only for a subpopulation of p53 wild type glioblastoma patients.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7

et al. 2011

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“…Increased CTSL levels have been identified in multiple tumor types and associated with short survival of several types of cancer. In addition to its well-established roles in development, growth and carcinogenesis, CTSL has been implicated in drug resistance (7)(8)(9). In a recent study, CTSL was overexpressed in ovarian cancer (10); however, no research regarding the association between CTSL with paclitaxel resistance in ovarian cancer has been performed thus far.…”

Section: Introductionmentioning

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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“…Cathepsin L seems to be involved in these processes (Lankelma et al 2010). Indeed, the active isoforms of cathepsin L can be found, not only intracellularly (liposomes, cytoplasm and nucleus) but also in the extracellular matrix (Zheng et al 2009). Owing to an increase in anaerobic glycolysis, the tumour cells are in an acidic environment (Lankelma et al 2010).…”

Section: S Verissimo Et Al: Novel Neuroblastoma Targetsmentioning

confidence: 99%

“…In vitro and in vivo studies have shown that the inhibition of cathepsin L not only reversed but also prevents the development of drug resistance (Zheng et al 2009). It has been suggested that the inhibition of cathepsin L allows the stabilisation and increase in availability of the drug target (Zheng et al 2009). …”

Section: S Verissimo Et Al: Novel Neuroblastoma Targetsmentioning

confidence: 99%

Neuroblastoma therapy: what is in the pipeline?

Veríssimo¹,

Molenaar²,

Fitzsimons³

et al. 2011

Endocrine-Related Cancer

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Despite the expansion of knowledge about neuroblastoma (NB) in recent years, the therapeutic outcome for children with a high-risk NB has not significantly improved. Therefore, more effective therapies are needed. This might be achieved by aiming future efforts at recently proposed but not yet developed targets for NB therapy. In this review, we discuss the recently proposed molecular targets that are in clinical trials and, in particular, those that are not yet explored in the clinic. We focus on the selection of these molecular targets for which promising in vitro and in vivo results have been obtained by silencing/inhibiting them. In addition, these selected targets are involved at least in one of the NB tumorigenic processes: proliferation, anti-apoptosis, angiogenesis and/or metastasis. In particular, we will review a recently proposed target, the microtubule-associated protein (MAP) encoded by doublecortin-like kinase gene (DCLK1). DCLK1-derived MAPs are crucial for proliferation and survival of neuroblasts and are highly expressed not only in NB but also in other tumours such as gliomas. Additionally, we will discuss neuropeptide Y, its Y2 receptor and cathepsin L as examples of targets to decrease angiogenesis and metastasis of NB. Furthermore, we will review the micro-RNAs that have been proposed as therapeutic targets for NB. Detailed investigation of these not yet developed targets as well as exploration of multi-target approaches might be the key to a more effective NB therapy, i.e. increasing specificity, reducing toxicity and avoiding long-term side effects.

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Cathepsin L inhibition suppresses drug resistance in vitro and in vivo: a putative mechanism

Cited by 53 publications

References 34 publications

Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7

Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7

Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy

Neuroblastoma therapy: what is in the pipeline?

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