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Synergetic and Antagonistic Molecular Effects Mediated by the Feedback Loop of p53 and JNK between Saikosaponin D and SP600125 on Lung Cancer A549 Cells
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-09-12 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00595 Xiaoman Chen 1 , Chenglin Liu 1 , Ruilin Zhao 1 , Ping Zhao 1 , Ju Wu 1 , Nanjin Zhou 2 , Muying Ying 1, 2
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-09-12 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00595 Xiaoman Chen 1 , Chenglin Liu 1 , Ruilin Zhao 1 , Ping Zhao 1 , Ju Wu 1 , Nanjin Zhou 2 , Muying Ying 1, 2
Affiliation
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We jointly analyzed the changes in cell cycle arrest and distribution, the accumulation of subphase cells, apoptosis, and proliferation in A549 cells treated with Saikosaponin D (Ssd) and JNK inhibitor SP600125 alone or in combination. Our results indicated that cell cycle arrest at G0/G1, S, and G2/M phases was coupled with the accumulation of subG1, subS, and subG2 cells, corresponding to early apoptosis, DNA endoreplication, and later inhibitory proliferation, respectively. Analyzing the expression of 18 cell cycle regulatory genes and JNK and phosphorylated JNK (pJNK) levels revealed an enhancement in these factors by Ssd. Additional SP600125 weakened or eliminated the Ssd-induced increase of these factors except that p53/p21 and Rassfia levels were further improved. Ingenuity Pathway Analysis (IPA) of the interactions of these factors revealed a negative synergistic effect on apoptosis while a positive synergistic effect on proliferative inhibition of the two drugs: (1) Ssd induced apoptosis via the activation of two axes, TGFα-JNK-p53 and TGFα-Rassfia-Mst1. By eliminating the Ssd-induced increase of JNK/pJNK, additional SP600125 weakened the Ssd-induced apoptotic axis of TGFα-JNK-p53 and simultaneously abolished Ssd-induced apoptosis; (2) Ssd inhibited proliferation by the activation of two axes, TGFβ-p53/p21/p27/p15/p16 and TGFα-Rassfia-cyclin D1. By improving the Ssd-induced increase of p53/p21 and Rassfia, additional SP600125 enhanced the two axes of Ssd-induced inhibitory proliferation. Analyzing JNK/pJNK, p53, phospho-p53, and TNF-α levels revealed an opposite association of JNK/pJNK with p53 while consistent with phospho-p53 and TNF-α, which supported the proposals that JNK/pJNK negatively regulated p53 level, while it mediated p53 phosphorylation to transcriptionally activate TNF-α expression of apoptotic gene and trigger apoptosis. With the multiple roles, JNK/pJNK forms a synergetic and antagonistic feedback loop with phospho-p53/p53. Within the feedback loop, (1) Ssd-induced apoptosis depended on JNK/pJNK activities mediating phospho-p53 that activated TNF-α expression; (2) by weakening the negative regulation of JNK/pJNK in p53, SP600125 enhanced p53 level and the Ssd-induced inhibitory proliferation axes of TGFβ-p53/p21/p27/p15/p16. The results indicated the central coordinating roles of the feedback loop in the synergistic and antagonistic effects of the two drugs in A549 cells and provided a rationale for the combination of Ssd with SP600125 in the treatment of lung cancer.
中文翻译：
皂苷D和SP600125之间p53和JNK反馈环介导的协同和拮抗分子作用对肺癌A549细胞的影响
我们联合分析了单独或联合使用Saikosaponin D（Ssd）和JNK抑制剂SP600125处理的A549细胞在细胞周期停滞和分布，亚相细胞积累，凋亡和增殖方面的变化。我们的结果表明，细胞周期停滞在G0 / G1，S和G2 / M期与subG1，subS和subG2细胞的积累有关，分别对应于早期凋亡，DNA内复制和后来的抑制性增殖。分析18个细胞周期调控基因的表达以及JNK和磷酸化的JNK（pJNK）水平，发现Ssd增强了这些因子。额外的SP600125减弱或消除了Ssd诱导的这些因素的增加，但p53 / p21和Rassfia的水平进一步提高了。这些因素相互作用的创造力路径分析（IPA）显示了对细胞凋亡的负协同作用，而对两种药物的增殖抑制具有正协同作用：（1）Ssd通过激活TGFα-JNK-p53这两个轴激活了凋亡和TGFα-Rassfia-Mst1。通过消除Ssd诱导的JNK / pJNK的增加，额外的SP600125减弱了Ssd诱导的TGFα-JNK-p53的凋亡轴，同时废除了Ssd诱导的凋亡。（2）Ssd通过激活TGFβ-p53/ p21 / p27 / p15 / p16和TGFα-Rassfia-cyclinD1这两个轴来抑制增殖。通过改善Ssd诱导的p53 / p21和Rassfia的增加，额外的SP600125增强了Ssd诱导的抑制性增殖的两个轴。分析JNK / pJNK，p53，磷酸化p53，TNF-α水平显示JNK / pJNK与p53有相反的关联，而与磷酸p53和TNF-α一致，这支持了JNK / pJNK负调控p53水平的建议，而它介导p53磷酸化以转录激活TNF-α。凋亡基因的表达并触发凋亡。JNK / pJNK具有多种作用，可与磷酸化p53 / p53形成协同和拮抗的反馈环。在反馈回路内，（1）Ssd诱导的凋亡依赖于介导磷酸化p53的JNK / pJNK活性，该磷酸化激活p53激活TNF-α的表达。（2）通过减弱J53 / pJNK在p53中的负调控，SP600125增强了p53水平和Ssd诱导的TGFβ-p53/ p21 / p27 / p15 / p16的抑制增殖轴。
更新日期：2018-09-12
中文翻译：
皂苷D和SP600125之间p53和JNK反馈环介导的协同和拮抗分子作用对肺癌A549细胞的影响
我们联合分析了单独或联合使用Saikosaponin D（Ssd）和JNK抑制剂SP600125处理的A549细胞在细胞周期停滞和分布，亚相细胞积累，凋亡和增殖方面的变化。我们的结果表明，细胞周期停滞在G0 / G1，S和G2 / M期与subG1，subS和subG2细胞的积累有关，分别对应于早期凋亡，DNA内复制和后来的抑制性增殖。分析18个细胞周期调控基因的表达以及JNK和磷酸化的JNK（pJNK）水平，发现Ssd增强了这些因子。额外的SP600125减弱或消除了Ssd诱导的这些因素的增加，但p53 / p21和Rassfia的水平进一步提高了。这些因素相互作用的创造力路径分析（IPA）显示了对细胞凋亡的负协同作用，而对两种药物的增殖抑制具有正协同作用：（1）Ssd通过激活TGFα-JNK-p53这两个轴激活了凋亡和TGFα-Rassfia-Mst1。通过消除Ssd诱导的JNK / pJNK的增加，额外的SP600125减弱了Ssd诱导的TGFα-JNK-p53的凋亡轴，同时废除了Ssd诱导的凋亡。（2）Ssd通过激活TGFβ-p53/ p21 / p27 / p15 / p16和TGFα-Rassfia-cyclinD1这两个轴来抑制增殖。通过改善Ssd诱导的p53 / p21和Rassfia的增加，额外的SP600125增强了Ssd诱导的抑制性增殖的两个轴。分析JNK / pJNK，p53，磷酸化p53，TNF-α水平显示JNK / pJNK与p53有相反的关联，而与磷酸p53和TNF-α一致，这支持了JNK / pJNK负调控p53水平的建议，而它介导p53磷酸化以转录激活TNF-α。凋亡基因的表达并触发凋亡。JNK / pJNK具有多种作用，可与磷酸化p53 / p53形成协同和拮抗的反馈环。在反馈回路内，（1）Ssd诱导的凋亡依赖于介导磷酸化p53的JNK / pJNK活性，该磷酸化激活p53激活TNF-α的表达。（2）通过减弱J53 / pJNK在p53中的负调控，SP600125增强了p53水平和Ssd诱导的TGFβ-p53/ p21 / p27 / p15 / p16的抑制增殖轴。
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