Vitamin C kills thyroid cancer cells through ROS-dependent inhibition of MAPK/ERK and PI3K/AKT pathways via distinct mechanisms
Vitamin C kills thyroid cancer cells through ROS-dependent inhibition of MAPK/ERK and PI3K/AKT pathways via distinct mechanisms
复制标题
维生素 C 通过不同的机制，通过 ROS 依赖性抑制 MAPK/ERK 和 PI3K/AKT 通路来杀死甲状腺癌细胞
DOI：
10.7150/thno.35219
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Hou, Peng
中科院分区：
文献类型：
--
作者：
Su, Xi;Shen, Zhen;Hou, Peng
背景：维生素C已被证明可以选择性地杀死BRAF突变型结直肠癌细胞。BRAF突变是甲状腺肿瘤发生和发展中最常见的基因改变；然而，维生素C对甲状腺癌的抗肿瘤作用仍有待探索。方法：采用MTT法和流式细胞术观察维生素C对甲状腺癌细胞增殖和凋亡的影响。采用异种移植和转基因小鼠模型研究了维生素C在体内的抗肿瘤活性，并采用分子和生化方法探讨了维生素C在甲状腺癌中的抗肿瘤作用机制。结果：药物浓度的维生素C可显著抑制甲状腺癌细胞增殖，诱导细胞凋亡，与BRAF突变状态无关。我们证明了高剂量腹腔注射后血浆中维生素C水平的升高可显著抑制异种移植肿瘤的生长。在转基因小鼠模型中也得到了类似的结果。在机制上，维生素C通过ros介导的EGF/EGFR-MAPK/ERK信号活性的降低和AKT泛素化和降解的增加来根除BRAF野生型甲状腺癌细胞。另一方面，维生素C通过抑制atp依赖的MAPK/ERK信号的活性，并通过ros依赖途径诱导AKT的蛋白酶体降解，从而在BRAF突变型甲状腺癌细胞中发挥抗肿瘤活性。结论：我们的数据表明维生素C通过ros依赖机制抑制MAPK/ERK和PI3K/AKT通路杀死甲状腺癌细胞，提示维生素C药物浓度在甲状腺癌治疗中具有潜在的临床应用价值。
Background: Vitamin C has been demonstrated to kill BRAF mutant colorectal cancer cells selectively. BRAF mutation is the most common genetic alteration in thyroid tumor development and progression; however, the antitumor efficacy of vitamin C in thyroid cancer remains to be explored.Methods: The effect of vitamin C on thyroid cancer cell proliferation and apoptosis was assessed by the MTT assay and flow cytometry. Xenograft and transgenic mouse models were used to determine its in vivo antitumor activity of vitamin C. Molecular and biochemical methods were used to elucidate the underlying mechanisms of anticancer activity of vitamin C in thyroid cancer.Results: Pharmaceutical concentration of vitamin C significantly inhibited thyroid cancer cell proliferation and induced cell apoptosis regardless of BRAF mutation status. We demonstrated that the elevated level of Vitamin C in the plasma following a high dose of intraperitoneal injection dramatically inhibited the growth of xenograft tumors. Similar results were obtained in the transgenic mouse model. Mechanistically, vitamin C eradicated BRAF wild-type thyroid cancer cells through ROS-mediated decrease in the activity of EGF/EGFR-MAPK/ERK signaling and an increase in AKT ubiquitination and degradation. On the other hand, vitamin C exerted its antitumor activity in BRAF mutant thyroid cancer cells by inhibiting the activity of ATP-dependent MAPK/ERK signaling and inducing proteasome degradation of AKT via the ROS-dependent pathway.Conclusions: Our data demonstrate that vitamin C kills thyroid cancer cells by inhibiting MAPK/ERK and PI3K/AKT pathways via a ROS-dependent mechanism and suggest that pharmaceutical concentration of vitamin C has potential clinical use in thyroid cancer therapy.