Shikonin induces apoptosis of lung cancer cells via activation of FOX03a/EGR1/SIRT1 signaling antagonized by p300
Shikonin induces apoptosis of lung cancer cells via activation of FOX03a/EGR1/SIRT1 signaling antagonized by p300
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DOI：
10.1016/j.bbamcr.2016.07.005
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发表时间：
2016-11-01
影响因子：
5.1
通讯作者：
Chung, Kyung-Sook
中科院分区：
文献类型：
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作者：
Jeung, Yun-Ji;Kim, Han-Gyeul;Chung, Kyung-Sook
紫草素衍生物具有强大的细胞毒作用，包括诱导细胞凋亡。在这里，我们使用几个非小细胞肺癌(NSCLC)细胞系，在不影响体重的异种移植模型中证明了紫草素的体内细胞毒性作用以及其对细胞存活率的降低。我们发现紫草素抑制ART激活了Forkhead box(Fox)O3a/早期生长反应蛋白(EGR)1信号通路，并增强了靶基因Bim的表达，从而导致肺癌细胞的凋亡。FOXOa野生型或结构活性突变体的过表达增强了紫草素诱导的Bim表达。依赖NAD(+)的组蛋白去乙酰化酶sirtuin(SIRT)1通过去乙酰化FOXO3a，使Egr1与Bim启动子结合并激活Bim表达，从而放大促凋亡作用。同时，亚致死剂量的紫草素可使PI3K/AKT活性增强，FOXO3a活性降低，p300表达上调。P300过表达促进FOXO3a乙酰化，而紫草素诱导的Bim表达被p300过表达抑制，从而促进细胞存活。P300过表达和SIRT1抑制剂处理可增加FOXO3a乙酰化，提高细胞存活率。此外，紫草素诱导的FOXO3a核定位可被ART激活和SIRT1抑制所阻断，从而阻断Bim的表达并对紫草素的细胞毒作用产生抵抗作用。SIRT1抑制剂可恢复紫草素引起的EGR1升高。这些结果提示紫草素通过激活FOXO3a/Egr1/SIRT1信号通路诱导某些肺癌细胞的凋亡，而ART和p300通过上调Bim负向调节这一过程。(C)2016年，由爱思唯尔出版。
Shikonin derivatives exert powerful cytotoxic effects including induction of apoptosis. Here, we demonstrate the cytotoxic efficacy of shikonin in vivo in xenograft models, which did not affect body weight as well as its reduction of cell viability in vitro using several non-small cell lung cancer (NSCLC) cell lines. We found that inhibition of ART by shikonin activated the forkhead box (FOX)O3a/early growth response protein (EGR)1 signaling cascade and enhanced the expression of the target gene Bim, leading to apoptosis in lung cancer cells. Overexpression of wild-type or a constitutively active mutant of FOXOa enhanced shikonin-induced Bim expression. The NAD(+)-dependent histone deacetylase sirtuin (SIRT)1 amplified the pro-apoptotic effect by deacetylating FOXO3a, which induced EGR1 binding to the Bim promoter and activated Bim expression. Meanwhile, PI3K/AKT activity was enhanced, whereas that of FOXO3a was reduced and p300 was upregulated by treatment with a sublethal dose of shikonin. FOXO3a acetylation was enhanced by p300 overexpression, while shikonin-induced Bim expression was suppressed by p300 overexpression, which promoted cell survival. FOXO3a acetylation was increased by p300 overexpression and treatment with SIRT1 inhibitor, improving cell survival. In addition, shikonin-induced FOXO3a nuclear localization was blocked by ART activation and SIRT1 inhibition, which blocked Bim expression and conferred resistance to the cytotoxic effects of shikonin. The EGR1 increase induced by shikonin was restored by pretreatment with SIRT1 inhibitor. These results suggest that shikonin induces apoptosis in some lung cancer cells via activation of FOXO3a/EGR1/SIRT1 signaling, and that ART and p300 negatively regulate this process via Bim upregulation. (C) 2016 Published by Elsevier B.V.