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

Fang Yang; Wang-wang Liu; Hui Chen; Jia Zhu; Ai-hua Huang; Fei Zhou; Yi Gan; Yan-hua Zhang; Li MA

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

Author: Fang YANG ¹ ; Wang-Wang LIU ¹ ; Hui CHEN ¹ ; Jia ZHU ¹ ; Ai-Hua HUANG ¹ ; Fei ZHOU ² ; Yi GAN ¹ ; Yan-Hua ZHANG ¹ ; Li MA ³
Author Information

1. Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
2. Department of Radiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
3. Department of Neurosurgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
Publication Type:Journal Article
Keywords: Carfilzomib; Lung adenocarcinoma; Gadd45a; Cell cycle arrest; Apoptosis
MeSH: Adenocarcinoma of Lung/pathology*; Apoptosis/drug effects*; Cell Cycle Checkpoints/drug effects*; Cell Cycle Proteins/genetics*; Cell Line, Tumor; Forkhead Box Protein O3/physiology*; Gene Expression Regulation, Neoplastic/drug effects*; Humans; Lung Neoplasms/pathology*; Oligopeptides/pharmacology*; Proto-Oncogene Proteins c-akt/physiology*; Up-Regulation
From: Journal of Zhejiang University. Science. B 2020;21(1):64-76
CountryChina
Language:English
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.