Abstract
Resistance to platinum-based combination chemotherapy is the main cause of poor prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC). Previously, we showed that CACNA2D3 (voltage-dependent subunit alpha 2 delta 3 of a calcium channel complex) was significantly downregulated and functioned as a tumor suppressor in ESCC, but its role in the chemosensitivity of ESCC to cisplatin remained unknown. Here, we found that the expression of CACNA2D3 was significantly associated with poor platinum response in ESCC patients from the Gene Expression Omnibus database. Overexpression of CACNA2D3 increased sensitivity to cisplatin in ESCC in vitro, whereas knockdown of CACNA2D3 increased cisplatin resistance. CACNA2D3 promoted cisplatin-induced apoptosis by modulating intracellular Ca2+ stores. In vivo experiments further showed that overexpression of CACNA2D3 enhanced cisplatin anti-tumor effects in a xenograft mouse model. CACNA2D3 overexpression also resulted in the attenuation of PI3K and Akt phosphorylation. Treatment with the PI3K/Akt inhibitor LY294002 restored the chemosensitivity of CACAN2D3-knockdown cells to cisplatin. In conclusion, the results of the current study indicate that CACAN2D3 enhances the chemosensitivity of ESCC to cisplatin via inducing Ca2+-mediated apoptosis and suppressing PI3K/Akt pathways. Therefore, regulating the expression of CACNA2D3 is a potential new strategy to increase the efficacy of cisplatin in ESCC patients.
Highlights
Esophageal cancer (EC) is a fatal digestive tract malignancy [1]
To analyze the relationship between the expression of CACNA2D3 and chemoresistance in esophageal squamous cell carcinoma (ESCC), we screened microarray data predicting the response of esophageal cancer patients to neoadjuvant chemotherapy from the Gene Expression Omnibus (GSE45670) [29]
We further investigated the association of CACNA2D3 expression with chemotherapeutic response in ESCC cell lines by calculating the IC50 values of cisplatin during treatment
Summary
Esophageal cancer (EC) is a fatal digestive tract malignancy [1]. EC is composed of two major histologic subtypes: adenocarcinoma and squamous cell carcinoma. Esophageal squamous cell carcinoma (ESCC) is more common in Southeast and Central Asia [2, 3]. Esophagectomy is the usual method for the treatment of early esophageal cancer. Most ESCC patients are diagnosed at an advanced stage when surgery is no longer effective. A cisplatinbased regimen is widely used as the first-line treatment in advanced ESCC [8,9,10]. Cisplatin chemotherapy is often limited by natural and acquired resistance. It is critical to identify potential resistance mechanisms in order to restore tumor cell sensitivity to cisplatin
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