Abstract：
Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer and is highly malignant with high chemoresistance. CACNA1H is pivotal in tumor development. However, the role of CACNA1H in the acquisition process of chemotherapeutic resistance in OCCC cells is rarely reported. Therefore, this study aimed to explore the role of CACNA1H in chemotherapy resistance of OCCC cells and its related mechanism. Based on bioinformatics analysis, we found that CACNA1H was downregulated in chemoresistant OCCC patients compared to chemosensitive OCCC patients. Comparing DDP-resistant and sensitive OCCC cell lines, the resistant strain showed lower CACNA1H mRNA expression. CACNA1H expression was associated with calcium signaling pathways in chemoresistant OCCC patients. CACNA1H mRNA expression was significantly downregulated in OCCC cells compared to normal ovarian epithelial cells. When CACNA1H was overexpressed, intracellular Ca2+ concentration and protein levels of p-CaMKII and p-Akt were significantly upregulated, while protein levels of LC3-II/LC3-I and Beclin1 were downregulated, indicating a repression of autophagy. The rescue experiment revealed that CACNA1H overexpression in drug-resistant OCCC cells reduced autophagy-induced DDP resistance via CaMKII/Akt signaling. Overall, CACNA1H increased intracellular Ca2+ concentration and activated CaMKII/Akt signaling pathway in OCCC, thereby repressing autophagy to maintain the sensitivity of OCCC cells to DDP.
摘要：
卵巢透明细胞癌（OCCC）是卵巢癌的一种亚型，恶性程度高，耐药性高。CACNA1H在肿瘤的发展中起着关键作用。然而,CACNA1H在OCCC细胞化疗耐药获得过程中的作用鲜有报道。因此,本研究旨在探讨CACNA1H在OCCC细胞化疗耐药中的作用及相关机制。基于生物信息学分析，我们发现,与化疗敏感型OCCC患者相比,CACNA1H在化疗耐药型OCCC患者中下调.比较DDP抗性和敏感的OCCC细胞系，抗性菌株显示较低的CACNA1HmRNA表达。CACNA1H表达与化疗耐药OCCC患者钙信号通路相关。与正常卵巢上皮细胞相比，OCCC细胞中CACNA1HmRNA的表达显着下调。当CACNA1H过表达时，p-CaMKII和p-Akt的细胞内Ca2+浓度和蛋白水平显著上调,而LC3-II/LC3-I和Beclin1的蛋白质水平下调，表明自噬的抑制。拯救实验表明，耐药OCCC细胞中的CACNA1H过表达通过CaMKII/Akt信号传导降低了自噬诱导的DDP抗性。总的来说,CACNA1H增加细胞内Ca2+浓度和激活的CaMKII/Akt信号通路，从而抑制自噬以维持OCCC细胞对DDP的敏感性。
