Abstract
Osteosarcoma is the most common malignant bone tumor. Chloride (Cl−) channels-mediated Cl− movement plays an important role in regulating the functions of various cancer cells, but its role in osteosarcoma remains unclear. In this study, we found that ClC-5 was increased in osteosarcoma tissues compared with normal bone tissues. Patients with high ClC-5 expression showed poor overall survival relative to those patients with low ClC-5 expression. Higher ClC-5 expression and lower intracellular Cl− concentration ([Cl−]i) were observed in osteosarcoma cells compared with normal osteoblasts. Lowering [Cl−]i increased the viability of osteosarcoma cells, which was markedly blocked by ClC-5 downregulation. Knockdown of ClC-5 significantly induced osteosarcoma cell apoptosis and increased the release of cytochrome c from mitochondria to cytosol, concomitantly with cleavage of caspase-9, caspase-3, and PARP. The effect of ClC-5 downregulation on osteosarcoma cell apoptosis and viability was abolished by caspase-3 and caspase-9 inhibitors, but not caspase-8 inhibitor. Furthermore, ClC-5 inhibition promoted Bax translocation from cytosol to mitochondria. Immunoprecipitation showed that ClC-5 interacted with Bax and ClC-5 downregulation enhanced Bax and tBid complex formation. Collectively, we demonstrate that ClC-5 downregulation induces osteosarcoma cell apoptosis via mitochondria-dependent apoptotic pathway activation by promoting Bax and tBid association and subsequent Bax translocation.
Highlights
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents [1]
To further determine the relationship between ClC-5 expression and the clinic pathologic characteristics of osteosarcoma patients, the patients were divided into low expression group and high expression group according to the median expression of ClC-5
We found overexpression of ClC-5 in osteosarcoma tissues compared to normal bone tissues
Summary
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents [1]. It accounts for about 20% of primary bone cancer and 2.4% of all malignancies in pediatric patients [2]. Osteosarcoma patients usually receive a three-drug chemotherapy regimen consisting of cisplatin, doxorubicin, and methotrexate, followed by surgical resection of the primary tumor in which higher survival rates have been achieved [3, 4]. Some patients are diagnosed with advanced cancer at the first diagnosis. The therapeutic effects of surgery in this stage are poor due to the distant metastasis [1]. It may be of great importance to understand the molecular
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