Theranostics 2019; 9(15):4461-4473. doi:10.7150/thno.35219

Research Paper

Vitamin C kills thyroid cancer cells through ROS-dependent inhibition of MAPK/ERK and PI3K/AKT pathways via distinct mechanisms

Xi Su1,#, Zhen Shen2,#, Qi Yang1, Fang Sui1, Jun Pu1, Jingjing Ma1, Sharui Ma1, Demao Yao3, Meiju Ji4,✉, Peng Hou1,✉

1. Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
2. Department of Otolaryngology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
3. Department of Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
4. Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
# These authors contributed equally to this work.

Abstract

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.

Keywords: Vitamin C, thyroid cancer, ROS, BRAF mutation, PI3K/AKT pathway

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How to cite this article:
Su X, Shen Z, Yang Q, Sui F, Pu J, Ma J, Ma S, Yao D, Ji M, Hou P. Vitamin C kills thyroid cancer cells through ROS-dependent inhibition of MAPK/ERK and PI3K/AKT pathways via distinct mechanisms. Theranostics 2019; 9(15):4461-4473. doi:10.7150/thno.35219. Available from http://www.thno.org/v09p4461.htm