Induction of apoptosis and autophagy in metastatic thyroid cancer cells by valproic acid (VPA).
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.
Department of Surgical Oncology, The 2nd Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.
Yuan
Y
Xu
Department of Operating Room, The 1st Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.
Duo
D
Xu
Department of Neck Surgery, The 2nd Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.
Shao-Jun
SJ
Zhu
Department of Neck Surgery, The 2nd Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.
Bing
B
Ye
Department of Neck Surgery, The 2nd Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.
Jian-Da
JD
Dong
Department of Neck Surgery, The 2nd Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.
Yin-Long
YL
Zhang
Department of Neck Surgery, The 2nd Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.
Yi
Y
Zhang
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014635:Valproic Acid; D002738:Chloroquine; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
Apoptosis; cytotoxicity; inhibited; metastasis; oxidative stress