Cucurbitacin IIa: a novel class of anti-cancer drug inducing non-reversible actin aggregation and inhibiting survivin independent of JAK2/STAT3 phosphorylation.
Cucurbitacin IIa: a novel class of anti-cancer drug inducing non-reversible actin aggregation and inhibiting survivin independent of JAK2/STAT3 phosphorylation.
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DOI：
10.1038/bjc.2011.10
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发表时间：
2011-03-01
影响因子：
8.8
通讯作者：
Lu, Q.
中科院分区：
文献类型：
--
作者：
Boykin, C.;Zhang, G.;Chen, Y-H;Zhang, R-W;Fan, X-E;Yang, W-M;Lu, Q.
葫芦素（Cuc）和三萜衍生的天然产物除了具有显著的抗菌和抗炎活性外，还具有抗癌潜力。最近，Janus激酶2（JAK 2）/信号转导子和转录激活子3（STAT 3）信号传导的抑制被证明是Cuc家族诱导癌症细胞死亡的作用的基础。我们纯化了Cuc IIa，从药用植物雪胆的活性成分，它显示出不同的结构修饰从其他Cuc衍生物。我们研究了其在体外对癌细胞的抑制作用和在体内肿瘤生长的机制。Cuc Ⅱ a诱导丝状肌动蛋白的不可逆聚集，并通过增加G2/M期群体来阻滞细胞周期。Cuc IIa导致磷酸化组蛋白H3减少，聚-（ADP-核糖）聚合酶或PARP的切割显著增加，直接上游的DNA断裂作为半胱天冬酶激活的结果，与有丝分裂阻滞诱导的细胞死亡一致。然而，与其他Cuc成员不同，Cuc IIa不抑制JAK 2/STAT 3磷酸化或改变促分裂原活化蛋白激酶的磷酸化。相反，细胞周期调节的凋亡蛋白抑制剂（IAP）生存素的表达减少。引入癌蛋白δ-连环蛋白，增加生存素表达并抑制小GTdR RhoA，降低了Cuc IIa诱导细胞死亡的功效。支持Cuc IIa对肌动蛋白细胞骨架信号传导的影响，RhoA磷酸化减少，表明其活性增加。Cuc IIa是一类新型抗癌药物，通过破坏肌动蛋白细胞骨架并通过抑制JAK 2/STAT 3下游的存活素来指导细胞经历PARP介导的凋亡来抑制癌细胞扩增。
Cucurbitacin (Cuc) and triterpene-derived natural products exhibit anti-cancer potential in addition to their conspicuous anti-bacterial and anti-inflammatory activity. Recently, inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling was shown to underlie the effects of Cuc family on inducing cell death in cancer. We purified Cuc IIa, the active component from the medicinal plant Hemsleya amalils Diels, which shows different structural modifications from other Cuc derivatives. We investigated the mechanisms of its inhibitory effects on cancer cells in vitro and tumour growth in vivo. Cuc IIa induced the irreversible clustering of filamentous actin and arrested cell cycle by the increases in G2/M populations. Cuc IIa resulted in the reduced phospho-Histone H3 and markedly increased cleavage of poly-(ADP-ribose) polymerase or PARP, immediate upstream of DNA breakdown as the result of caspase activation, consistent with mitotic blockage-induced cell death. However, unlike other Cuc members, Cuc IIa did not suppress JAK2/STAT3 phosphorylation or alter phosphorylation of mitogen-activated protein kinases. Instead, the expression of the cell cycle-regulated Inhibitor of Apoptosis Protein (IAP) survivin was reduced. Introducing oncoprotein δ-catenin, which increased survivin expression and suppressed small GTPase RhoA, reduced efficacy of Cuc IIa to induce cell death. Supporting the effects of Cuc IIa on actin cytoskeletal signaling, RhoA phosphorylation was reduced suggesting its increased activity. Cuc IIa is a novel class of anti-cancer drug in suppression of cancer cell expansion by disrupting the actin cytoskeleton and directing the cell to undergo PARP-mediated apoptosis through the inhibition of survivin downstream of JAK2/STAT3.
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