Cryptotanshinone activates p38/JNK and inhibits Erk1/2 leading to caspase-independent cell death in tumor cells.
Cryptotanshinone activates p38/JNK and inhibits Erk1/2 leading to caspase-independent cell death in tumor cells.
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DOI：
10.1158/1940-6207.capr-11-0551
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发表时间：
2012-05
期刊：
影响因子：
--
通讯作者：
Huang S
中科院分区：
文献类型：
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作者：
Chen W;Liu L;Luo Y;Odaka Y;Awate S;Zhou H;Shen T;Zheng S;Lu Y;Huang S
隐丹参酮(CPT)是从丹参中分离得到的一种天然化合物，是一种潜在的抗癌药物。然而，其潜在的机制还不是很清楚。在这里，我们发现CPT诱导人类肿瘤细胞(Rh30、DU145和MCF-7)中caspase非依赖的细胞死亡。CPT除下调抗凋亡蛋白Survivin和Mcl-1的表达外，还可上调p38丝裂原活化蛋白激酶(MAPK)和c-jun氨基末端激酶(JNK)的磷酸化，抑制细胞外信号调节激酶1/2(ERK1/2)的磷酸化。用SB202190抑制p38或用SP600125抑制JNK可减轻CPT诱导的细胞死亡。同样，沉默p38或c-jun也在一定程度上阻止了CPT诱导的细胞死亡。相反，结构性活性丝裂原活化蛋白激酶1(MKK1)的表达可抵抗CPT抑制ERK1/2磷酸化和诱导细胞死亡。此外，我们还发现所有这些都归因于CPT对活性氧物种(ROS)的诱导。结果表明，CPT诱导ROS呈浓度和时间依赖性，ROS清除剂N-乙酰-L半胱氨酸(NAC)抑制CPT诱导ROS，NAC减弱CPT对p38/JNK的激活，抑制ERK1/2，诱导细胞死亡。结果提示，CPT诱导ROS激活p38/JNK，抑制ERK1/2，导致肿瘤细胞caspase非依赖性死亡。
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.