Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Folma Road, Jin'an District, Fuzhou, 350014, Fujian, China.
Department of Abdominal Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
Mol Genet Genomics. 2024 Aug 6;299(1):77. doi: 10.1007/s00438-024-02165-y.
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 Ca 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 Ca concentration and activated CaMKII/Akt signaling pathway in OCCC, thereby repressing autophagy to maintain the sensitivity of OCCC cells to DDP.
卵巢透明细胞癌（OCCC）是卵巢癌的一种亚型，具有高度恶性和化疗耐药性。CACNA1H 在肿瘤发展中起着关键作用。然而，CACNA1H 在 OCCC 细胞获得化疗耐药性过程中的作用很少有报道。因此，本研究旨在探讨 CACNA1H 在 OCCC 细胞化疗耐药中的作用及其相关机制。基于生物信息学分析，我们发现与化疗敏感的 OCCC 患者相比，耐药的 OCCC 患者中 CACNA1H 表达下调。与 DDP 耐药和敏感 OCCC 细胞系相比，耐药株 CACNA1H mRNA 表达降低。CACNA1H 表达与耐药 OCCC 患者的钙信号通路有关。与正常卵巢上皮细胞相比，OCCC 细胞中 CACNA1H mRNA 表达显著下调。当 CACNA1H 过表达时，细胞内 Ca 浓度和 p-CaMKII 和 p-Akt 的蛋白水平显著升高，而 LC3-II/LC3-I 和 Beclin1 的蛋白水平降低，表明自噬受到抑制。挽救实验表明，耐药 OCCC 细胞中 CACNA1H 的过表达通过 CaMKII/Akt 信号通路降低自噬诱导的 DDP 耐药性。总之，CACNA1H 通过增加 OCCC 细胞内 Ca 浓度并激活 CaMKII/Akt 信号通路，抑制自噬来维持 OCCC 细胞对 DDP 的敏感性。
