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氟西汀通过p21相关通路增加顺铂对非小细胞肺癌细胞株的抗肿瘤作用 被引量:3

Inhibition of lung cancer cells growth by fluoxetine and cisplatin mediated through p21-dependent signaling pathway
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摘要 目的 探究氟西汀联合顺铂是否具有抗肺癌细胞的作用及其作用机制。方法 通过CCK8实验检测H460细胞株的细胞活力,并筛选合适的氟西汀和顺铂作用浓度;通过Transwell实验评估迁移和侵袭能力;通过流式细胞仪和免疫荧光染色检测细胞周期和细胞自噬;通过Western blot检测相关蛋白的表达;通过siRNA实验沉默p21表达,验证p21通路对氟西汀联合顺铂抗肿瘤作用的影响。结果 氟西汀和顺铂影响细胞增殖、迁移、侵袭能力,两药联合可以产生更明显的抑制作用。相较于顺铂组,联合组中G0/G1期细胞比例(32.96%±4.78%vs.24.51%±3.61%,P=0.042)及自噬增加,Western blot结果显示p21及LC3蛋白在联合组中增加更为明显。挽救实验发现,敲低p21减弱了氟西汀联合顺铂对细胞侵袭能力的抑制作用(26.00±6.16 vs. 60.33±7.59,P=0.004),同时降低了联合组中G0/G1期的百分比(52.46%±2.53%vs. 44.34%±3.32%,P=0.043),p21还通过影响p62蛋白进而影响自噬。结论 氟西汀可能通过p21依赖的信号传导通路增加顺铂对肺癌细胞的敏感性,为氟西汀作为临床辅助治疗提供了有力的实验依据。 Objective To explore the effectiveness of fluoxetine combined with cisplatin and to discover the potential mechanism of combination treatment. Methods In order to assess the cell viability and screen appropriate concentrations of fluoxetine and cisplatin, we performed the CCK8 assay on H460 cells. Transwell assay was used to analysis the ability of cell migration and invasion, and flow cytometry and immunofluorescent staining were implemented to detect cell cycle and autophagy, respectively. To further investigate the underlying mechanism, the expression of p21 was silenced by the tool of small interfering RNA and rescue experiments were applied to detect the effect of p21 on combination treatment. Results Compared with fluoxetine or cisplatin alone group, the proliferation, migration, and invasion of the combination group were obviously inhibited. Besides, the fluoxetine plus cisplatin increased the proportion of G0/G1 phase(32.96%±4.78% vs. 24.51%±3.61%,P=0.042) and autophagy.Compared with cisplatin alone, the Western bolt demonstrated that the combination treatment upregulated the expression levels of p21 and LC3. We further investigated the role of p21 and found that knockdown of p21 recovered the inhibition of invasion(26.00±6.16 vs. 60.33±7.59,P=0.004), while decreased the percentage of G0/G1 phase(52.46%±2.53% vs. 44.34%±3.32%,P=0.043). Interestingly, we discovered that the expression of p62 could also be inhibited by p21. Conclusion The anti-tumor and synergistic effect of fluoxetine via the p21-dependent signaling pathway, indicating the fluoxetine can be a potential agent to adjuvant therapies.
作者 邵莎莉 庄喜兵 乔田奎 SHAO Sha-li;ZHUANG Xi-bing;QIAO Tian-kui(Center for Tumor Diagnosis and Therapy,Jinshan Hospital,Fudan University,Shanghai 201508,China)
出处 《复旦学报(医学版)》 CAS CSCD 北大核心 2023年第1期48-56,共9页 Fudan University Journal of Medical Sciences
基金 上海市卫健委医学重点专科建设计划(ZK2019B30)。
关键词 氟西汀 顺铂 P21 细胞周期 自噬 fluoxetine cisplatin p21 cell cycle autophagy
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