Wang Changzheng, Lv Hongwei, Yang Wen, Li Ting, Fang Tian, Lv Guishuai, Han Qin, Dong Liwei, Jiang Tianyi, Jiang Beige, Yang Guangshun, Wang Hongyang
International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; Fifth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
Cancer Lett. 2017 Jul 10;398:1-11. doi: 10.1016/j.canlet.2017.03.039. Epub 2017 Apr 4.
Cholangiocarcinoma (CC) is a devastating malignancy with late diagnosis and poor response to conventional chemotherapy. Recent studies have revealed anti-cancer effect of vitamin C (l-ascorbic acid, ascorbate) in several types of cancer. However, the effect of l-ascorbic acid (AA) in CC remains elusive. Herein, we demonstrated that AA induced cytotoxicity in CC cells by generating intracellular reactive oxygen species (ROS), and subsequently DNA damage, ATP depletion, mTOR pathway inhibition. Moreover, AA worked synergistically with chemotherapeutic agent cisplatin to impair CC cells growth both in vitro and in vivo. Intriguingly, sodium-dependent vitamin C transporter 2 (SVCT-2) expression was inversely correlated with IC50 values of AA. Knockdown of SVCT-2 dramatically alleviated DNA damage, ATP depletion, and inhibition of mTOR pathway induced by AA. Furthermore, SVCT-2 knockdown endowed CC cells with the resistance to AA treatment. Finally, the inhibitory effects of AA were further confirmed in patient-derived CC xenograft models. Thus, our results unravel therapeutic potential of AA alone or in combination with cisplatin for CC. SVCT2 expression level may serve as a positive outcome predictor for AA treatment in CC.
胆管癌（CC）是一种具有毁灭性的恶性肿瘤，诊断较晚且对传统化疗反应不佳。最近的研究揭示了维生素C（L-抗坏血酸，抗坏血酸盐）在几种癌症中的抗癌作用。然而，L-抗坏血酸（AA）在胆管癌中的作用仍不清楚。在此，我们证明AA通过产生细胞内活性氧（ROS），随后导致DNA损伤、ATP耗竭、mTOR通路抑制，从而诱导胆管癌细胞的细胞毒性。此外，AA与化疗药物顺铂协同作用，在体外和体内均损害胆管癌细胞的生长。有趣的是，钠依赖性维生素C转运蛋白2（SVCT-2）的表达与AA的半数抑制浓度（IC50）值呈负相关。敲低SVCT-2可显著减轻AA诱导的DNA损伤、ATP耗竭和mTOR通路抑制。此外，SVCT-2敲低赋予胆管癌细胞对AA治疗的抗性。最后，在患者来源的胆管癌异种移植模型中进一步证实了AA的抑制作用。因此，我们的结果揭示了AA单独或与顺铂联合用于胆管癌的治疗潜力。SVCT2表达水平可能作为胆管癌中AA治疗的阳性结果预测指标。
