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CLC number: R734.2

On-line Access: 2020-01-03

Received: 2019-09-15

Revision Accepted: 2019-10-21

Crosschecked: 2019-11-18

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Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.1 P.64-76

http://doi.org/10.1631/jzus.B1900551


Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression


Author(s):  Fang Yang, Wang-Wang Liu, Hui Chen, Jia Zhu, Ai-Hua Huang, Fei Zhou, Yi Gan, Yan-Hua Zhang, Li Ma

Affiliation(s):  Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China; more

Corresponding email(s):   xiaoyangpumc@zju.edu.cn

Key Words:  Carfilzomib, Lung adenocarcinoma, Gadd45a, Cell cycle arrest, Apoptosis


Fang Yang, Wang-Wang Liu, Hui Chen, Jia Zhu, Ai-Hua Huang, Fei Zhou, Yi Gan, Yan-Hua Zhang, Li Ma. Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression[J]. Journal of Zhejiang University Science B, 2020, 21(1): 64-76.

@article{title="Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression",
author="Fang Yang, Wang-Wang Liu, Hui Chen, Jia Zhu, Ai-Hua Huang, Fei Zhou, Yi Gan, Yan-Hua Zhang, Li Ma",
journal="Journal of Zhejiang University Science B",
volume="21",
number="1",
pages="64-76",
year="2020",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B1900551"
}

%0 Journal Article
%T Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression
%A Fang Yang
%A Wang-Wang Liu
%A Hui Chen
%A Jia Zhu
%A Ai-Hua Huang
%A Fei Zhou
%A Yi Gan
%A Yan-Hua Zhang
%A Li Ma
%J Journal of Zhejiang University SCIENCE B
%V 21
%N 1
%P 64-76
%@ 1673-1581
%D 2020
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1900551

TY - JOUR
T1 - Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression
A1 - Fang Yang
A1 - Wang-Wang Liu
A1 - Hui Chen
A1 - Jia Zhu
A1 - Ai-Hua Huang
A1 - Fei Zhou
A1 - Yi Gan
A1 - Yan-Hua Zhang
A1 - Li Ma
J0 - Journal of Zhejiang University Science B
VL - 21
IS - 1
SP - 64
EP - 76
%@ 1673-1581
Y1 - 2020
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1900551


Abstract: 
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.

Carfilzomib通过上调Gadd45a表达抑制肺腺癌细胞生长

目的: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.
创新点: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.
方法: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.
结论: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

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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