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.

中文翻译：

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维生素C通过不同机制通过ROS依赖性抑制MAPK / ERK和PI3K / AKT途径杀死甲状腺癌细胞。

背景：维生素C已被证明可以选择性杀死BRAF突变型结直肠癌细胞。BRAF突变是甲状腺肿瘤发展和进展中最常见的遗传改变。然而，维生素C在甲状腺癌中的抗肿瘤功效仍有待探索。方法：采用MTT法和流式细胞术评估维生素C对甲状腺癌细胞增殖和凋亡的影响。使用异种移植和转基因小鼠模型确定其体内维生素C的抗肿瘤活性。使用分子和生化方法阐明维生素C在甲状腺癌中抗癌活性的潜在机制。结果：无论BRAF突变状态如何，药物浓度的维生素C均能显着抑制甲状腺癌细胞的增殖并诱导细胞凋亡。我们证明了大剂量腹膜内注射后血浆中维生素C含量的升高显着抑制了异种移植肿瘤的生长。在转基因小鼠模型中获得了相似的结果。从机理上讲，维生素C通过ROS介导的EGF / EGFR-MAPK / ERK信号活性降低以及AKT泛素化和降解增加而消除了BRAF野生型甲状腺癌细胞。另一方面，维生素C通过抑制ATP依赖性MAPK / ERK信号传导的活性并通过ROS依赖性途径诱导AKT蛋白酶体降解，从而在BRAF突变型甲状腺癌细胞中发挥其抗肿瘤活性。结论：