丙戊酸（VPA）诱导转移性甲状腺癌细胞凋亡和自噬
Induction of apoptosis and autophagy in metastatic thyroid cancer cells by valproic acid (VPA).
作者信息
Xu Yuan, Xu Duo, Zhu Shao-Jun, Ye Bing, Dong Jian-Da, Zhang Yin-Long, Zhang Yi
机构信息
Department of Surgical Oncology, The 2nd Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.
Department of Operating Room, The 1st Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.
出版信息
Int J Clin Exp Pathol. 2015 Jul 1;8(7):8291-7. eCollection 2015.
The present study investigated the effect of valproic acid (VPA) on the inhibition of RET signaling and induction of apoptosis in human thyroid carcinoma cells. VPA inhibited the viability of ARO and WRO cells and also inhibited cyclin D1 and caused caspase-3 cleavage. VPA decreased the level of RET protein and blocked the activation of RET downstream targets including phosphorylated ERK, phosphorylated AKT, and p70S6K/pS6. VPA induced metabolic stress, activated AMP-activated protein kinase and increased autophagic flux. Pharmacological inhibition of autophagy (chloroquine) augmented VPA-inducible cytotoxicity, suggesting that autophagy was protective in VPA-treated cells. VPA has a wide spectrum of activity against human thyroid carcinoma cells, and its cytotoxicity can be augmented by inhibiting autophagy. Expression of VPA molecular targets in metastatic human thyroid carcinoma cells suggests that VPA has a potential to become a thyroid cancer therapeutic agent.
本研究调查了丙戊酸（VPA）对人甲状腺癌细胞中RET信号传导抑制和细胞凋亡诱导的影响。VPA抑制了ARO和WRO细胞的活力，还抑制了细胞周期蛋白D1并导致半胱天冬酶-3裂解。VPA降低了RET蛋白水平，并阻断了包括磷酸化ERK、磷酸化AKT和p70S6K/pS6在内的RET下游靶点的激活。VPA诱导代谢应激，激活AMP激活的蛋白激酶并增加自噬通量。自噬的药理学抑制（氯喹）增强了VPA诱导的细胞毒性，表明自噬在VPA处理的细胞中具有保护作用。VPA对人甲状腺癌细胞具有广泛的活性谱，并且通过抑制自噬可增强其细胞毒性。VPA分子靶点在转移性人甲状腺癌细胞中的表达表明VPA有潜力成为一种甲状腺癌治疗药物。
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