Title:Cryptotanshinone Induces Pro-death Autophagy through JNK Signaling Mediated by Reactive Oxygen Species Generation in Lung Cancer Cells
Volume: 16
Issue: 5
Author(s): Wenhui Hao, Xuenong Zhang, Wenwen Zhao, Hong Zhu, Zhao-Yang Liu, Jinjian Lu and Xiuping Chen
Affiliation:
Keywords:
Autophagy, cancer, cryptotanshinone; JNK, reactive oxygen species.
Abstract: Cryptotanshinone (CTS), a natural product isolated from Salvia miltiorrhiza Bunge, demonstrates
anticancer effect. Previous reports showed that CTS induced caspase-independent cell death. Here, we reported
that CTS induced pro-death autophagy in human lung cancer cells. CTS inhibited the proliferation of A549 cells in
a time- and concentration- dependent manner. CTS triggered autophagy as confirmed by monodansylcadaverine
staining, transmission electron microscopy analysis, as well as western blot detection of microtubule-associated
protein light-chain 3 (LC3). CTS induced intracellular reactive oxygen species (ROS) formation in a
concentration- and time-dependent manner, which was reversed by N-acetyl-L-cysteine (NAC), catalase,
diphenyleneiodonium (DPI), pyrrolinodimethylthiocarbamate (PDTC), and dicumarol. Furthermore, CTS-induced autophagy was
inhibited by NAC, JNK siRNA and SP600125. NAC reversed CTS-induced JNK phosphorylation. NAC, 3-methyladenine (3-MA), and
SP600125 partly reversed CTS-induced cell death. In addition, CTS (10 mg/kg) dramatically inhibited tumor growth by 48.3% in A549
xenograft nude mice, which was completely reversed by NAC (50 mg/kg) co-treatment. Our findings showed that CTS induced pro-death
autophagy through activating JNK signaling mediated by increasing intracellular ROS production.