Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression
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Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm. There has been a lot of attention to applying these drugs for solid tumor treatment. Recent preclinical study has signified the effectiveness on cell proliferation inhibition in lung adenocarcinoma treated by carfilzomib (CFZ), a second generation proteasome inhibitor. However, no insight has been gained regarding the mechanism. In this study, we have systematically investigated the CFZ functions in cell proliferation and growth, cell cycle arrest, and apoptosis in lung adenocarcinoma cells. Flow cytometry experiments showed that CFZ significantly induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma. MTS and colony formation assays revealed that CFZ substantially inhibited survival of lung adenocarcinoma cells. All results were consistently correlated to the upregulation expression of Gadd45a, which is an important gene in modulating cell cycle arrest and apoptosis in response to physiologic and environmental stresses. Here, upregulation of Gadd45a expression was observed after CFZ treatment. Knocking down Gadd45a expression suppressed G2/M arrest and apoptosis in CFZ-treated cells, and reduced cytotoxicity of this drug. The protein expression analysis has further identified that the AKT/FOXO3a pathway is involved in Gadd45a upregulation after CFZ treatment. These findings unveil a novel mechanism of proteasome inhibitor in anti-solid tumor activity, and shed light on novel preferable therapeutic strategy for lung adenocarcinoma. We believe that Gadd45a expression can be a highly promising candidate predictor in evaluating the efficacy of proteasome inhibitors in solid tumor therapy.
Key wordsCarfilzomib Lung adenocarcinoma Gadd45a Cell cycle arrest Apoptosis
Carfilzomib 通过上调 Gadd45a 表达抑制肺腺癌细胞生长
最近有研究表明卡非佐米 (Carfilzominb, CFZ) 能有效抑制肺腺癌细胞生长, 但是其中的内在机制仍然需要进一步研究. 本文针对 CFZ 抑制肺腺癌生长机制进行了系统研究.
揭示了蛋白酶体抑制剂抗实体肿瘤的新机制, 为这类药物用于实体肿瘤治疗提供了有利依据. 同时 Gadd45a 可做为候选指标用于蛋白酶体抑制剂抗肿瘤疗效的预测.
应用流式细胞术检测 CFZ 对肺腺癌细胞周期和凋亡的影响; 通过 MTS 比色法及平板克隆形成实验分析 CFZ 对肺腺癌细胞生长的抑制作用; 使用蛋白质印迹法 (western blot) 和定量聚合酶链 反应 (qPCR) 检测相关基因表达水平的改变.
CFZ 通过 AKT/FOXO3a 通路上调 Gadd45a 基因的表达, 诱导肺腺癌细胞周期阻滞和凋亡, 从而发挥抗肿瘤效应.
关键词卡非佐米 (Carfilzomib) 肺腺癌 Gadd45a 细胞周期阻滞 凋亡
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We thank Dr. Li-feng FENG (Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China) for modifying the article.
Fang YANG conceived the research, designed the research, wrote and edited the manuscript. Fang YANG, Wangwang LIU, Hui CHEN, Jia ZHU, Ai-hua HUANG, Fei ZHOU, Yi GAN, Yan-hua ZHANG, and Li MA performed research; Fang YANG, Wang-wang LIU, and Hui CHEN analyzed the data. All authors read and approved the final manuscript. Therefore, all authors had full access to all the data in the study and take responsibility for the integrity and security of the data.
Compliance with ethics guidelines
Fang YANG, Wang-wang LIU, Hui CHEN, Jia ZHU, Ai-hua HUANG, Fei ZHOU, Yi GAN, Yan-hua ZHANG, and Li MA declare that they have no conflict of interest.
This article does not contain any studies with human or animal subjects performed by any of the authors.
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