Cryptotanshinone Induces Pro-death Autophagy through JNK Signaling Mediated by Reactive Oxygen Species Generation in Lung Cancer Cells.
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.
Wenhui
W
Hao
Xuenong
X
Zhang
Wenwen
W
Zhao
Hong
H
Zhu
Zhao-Yang
ZY
Liu
Jinjian
J
Lu
Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, China. xpchen@umac.mo.
Xiuping
X
Chen
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D010616:Phenanthrenes; D017382:Reactive Oxygen Species; C037886:cryptotanshinone; D048031:JNK Mitogen-Activated Protein Kinases