Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy

Abstract

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...

Identification Of The Molecular Targets And Immunophenotype Of Gastric Cancer By Bioinformatics Analysis

“…The elevated levels of CTSL might be associated to proliferation, invasion, metastasis and chemoresistance of cancer cells [18]. In addition, knockdown of CTSL could sensitize cancer cells to chemotherapy and target therapy [19,20]. Our study found that CTSL was up-regulated in gastric cancer compared to normal tissues, which is consistent with the ndings in previous studies [21].…”

A miRNA-200c/cathepsin L feedback loop determines paclitaxel resistance in human lung cancer A549 cells in vitro through regulating epithelial–mesenchymal transition

“…Zheng et al revealed that CTSL inhibition enhances the availability of cytoplasmic and nuclear protein drug targets, including estrogen receptor-α, Bcr-Abl, topoisomerase-IIα, histone deacetylase 1, and androgen receptor [9] . CTSL suppression also improves gefitinib resistance in non-small cell lung cancer [14] , and CTSL knockdown can increase the sensitivity of ovarian cancer cells to paclitaxel [38] . Our previous study also suggested that CTSL may be a novel therapeutic target to prevent tumor cells from becoming resistant to chemotherapy and to reinforce the efficiency of paclitaxel and cisplatin against lung cancer [12] .…”

The role of CIP2A as a therapeutic target of rapamycin in radioresistant head and neck cancer with TP53 mutation

“…10,15,25 Preclinical in vitro and in vivo studies have shown that CIP2A may regulate the proliferation, senescence, and apoptosis of multiple cancer cells [26][27][28] and contribute to resistance to chemotherapy such as cisplatin or docetaxel in solid tumors. [29][30][31] Therefore, CIP2A inhibition may serve as a promising modality to overcome chemoresistance. However, the role of CIP2A in radioresistance remains unclear, especially in HNSCC cells with p53 mutation.…”