Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) induces apoptosis and cell cycle arrest in A549 cells through p53 accumulation via c-Jun NH2-terminal kinase-mediated phosphorylation at serine 15 in vitro and in vivo
Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) induces apoptosis and cell cycle arrest in A549 cells through p53 accumulation via c-Jun NH2-terminal kinase-mediated phosphorylation at serine 15 in vitro and in vivo
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DOI：
10.1124/jpet.105.098863
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发表时间：
2006-08-01
影响因子：
3.5
通讯作者：
Lin, Chun-Ching
中科院分区：
文献类型：
--
作者：
Hsu, Ya-Ling;Cho, Chien-Yu;Lin, Chun-Ching
本研究首先研究了白花丹素（5-羟基-2-甲基-1,4-萘醌）对人非小细胞肺癌细胞 A549 的抗癌作用。白花丹素通过诱导癌细胞经历G(2)/M期停滞和凋亡而表现出有效的细胞生长抑制作用。细胞周期的阻断与 p21 水平升高和 cyclinB1、Cdc2 和 Cdc25C 量减少有关。白花丹素治疗还提高了灭活磷酸化 Cdc2 和 Cdc25C 的水平。通过显性失活 p53 转染阻断 p53 活性部分减少了白花丹素诱导的细胞凋亡和 G(2)/M 停滞，表明它可能是通过 p53 依赖性和独立途径进行操作的。白花丹素治疗触发了 Bax/Bcl-2 比率变化所表明的线粒体凋亡途径，导致线粒体膜电位损失、细胞色素 c 释放和 caspase-9 激活。我们还发现 c-Jun NH2 末端激酶 (JNK) 是白花丹素诱导的细胞生长抑制的关键介质。白花丹素激活 JNK，磷酸化 p53 的丝氨酸 15，从而通过减少 p53 和 MDM2 的相互作用来增加 p53 的稳定性。 SP600125（anthra[1,9-cd]pyrazol-6(2H)-one-1,9-pyrazoloanthrone）是 JNK 的一种特异性抑制剂，通过抑制 p53（丝氨酸 15）的磷酸化显着减少细胞凋亡，并随后增加 p53 和 MDM2 的相互作用。 SP6000125 还抑制白花丹素诱导的 Bcl-2 (Ser70) 磷酸化。进一步研究发现，白花丹素对细胞生长的抑制作用在裸鼠模型中也很明显。综上所述，这些结果表明 JNK 和 p53 在白花丹素诱导的人非小细胞肺癌细胞 G(2)/M 阻滞和细胞凋亡中发挥关键作用。
This study first investigates the anticancer effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) in human nonsmall cell lung cancer cells, A549. Plumbagin has exhibited effective cell growth inhibition by inducing cancer cells to undergo G(2)/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased levels of p21 and reduced amounts of cyclinB1, Cdc2, and Cdc25C. Plumbagin treatment also enhanced the levels of inactivated phosphorylated Cdc2 and Cdc25C. Blockade of p53 activity by dominant-negative p53 transfection partially decreased plumbagin-induced apoptosis and G(2)/M arrest, suggesting it might be operated by p53-dependent and independent pathway. Plumbagin treatment triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss, cytochrome c release, and caspase-9 activation. We also found that c-Jun NH2-terminal kinase (JNK) is a critical mediator in plumbagin-induced cell growth inhibition. Activation of JNK by plumbagin phosphorylated p53 at serine 15, resulting in increased stability of p53 by decreasing p53 and MDM2 interaction. SP600125 (anthra[1,9-cd] pyrazol-6(2H)-one-1,9-pyrazoloanthrone), a specific inhibitor of JNK, significantly decreased apoptosis by inhibiting the phosphorylation of p53 (serine 15) and subsequently increased the interaction of p53 and MDM2. SP6000125 also inhibited the phosphorylation of Bcl-2 (Ser70) induced by plumbagin. Further investigation revealed that plumbagin's inhibition of cell growth effect was also evident in a nude mice model. Taken together, these results suggest a critical role for JNK and p53 in plumbagin-induced G(2)/M arrest and apoptosis of human nonsmall cell lung cancer cells.