Cryptotanshinone Activates p38/JNK and Inhibits Erk1/2 Leading to Caspase-Independent Cell Death in Tumor Cells

被引:65
作者
Chen, Wenxing [1 ,3 ]
Liu, Lei [1 ]
Luo, Yan [1 ]
Odaka, Yoshinobu [1 ]
Awate, Sanket [1 ]
Zhou, Hongyu [1 ]
Shen, Tao [1 ]
Zheng, Shizhong [3 ]
Lu, Yin [3 ]
Huang, Shile [1 ,2 ]
机构
[1] Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Shreveport, LA 71130 USA
[2] Louisiana State Univ, Hlth Sci Ctr, Feist Weiller Canc Ctr, Shreveport, LA 71130 USA
[3] Nanjing Univ Chinese Med, Coll Pharm, Dept Clin Pharm, Nanjing 210029, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
INDUCED NEURONAL APOPTOSIS; PROTEIN PHOSPHATASE 2A; PROSTATE-CANCER CELLS; SALVIA-MILTIORRHIZA; SIGNALING PATHWAYS; P38; MAPK; MAMMALIAN TARGET; KINASE; GROWTH; EXPRESSION;
D O I
10.1158/1940-6207.CAPR-11-0551
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here, we show that CPT induced caspase-independent cell death in human tumor cells (Rh30, DU145, and MCF-7). Besides downregulating antiapoptotic protein expression of survivin and Mcl-1, CPT increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK), and inhibited phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2). Inhibition of p38 with SB202190 or JNK with SP600125 attenuated CPT-induced cell death. Similarly, silencing p38 or c-Jun also in part prevented CPT-induced cell death. In contrast, expression of constitutively active mitogen-activated protein kinase kinase 1 (MKK1) conferred resistance to CPT inhibition of Erk1/2 phosphorylation and induction of cell death. Furthermore, we found that all of these were attributed to CPT induction of reactive oxygen species (ROS). This is evidenced by the findings that CPT induced ROS in a concentration-and time-dependent manner; CPT induction of ROS was inhibited by N-acetyl-L-cysteine (NAC), a ROS scavenger; and NAC attenuated CPT activation of p38/JNK, inhibition of Erk1/2, and induction of cell death. The results suggested that CPT induction of ROS activates p38/JNK and inhibits Erk1/2, leading to caspase-independent cell death in tumor cells. Cancer Prev Res; 5(5); 778-87. (C)2012 AACR.
引用
收藏
页码:778 / 787
页数:10
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