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

• Published in: Journal of Zhejiang University. B. Science Vol. 21; no. 1; pp. 64 - 76
• Main Authors: Yang, Fang, Liu, Wang-wang, Chen, Hui, Zhu, Jia, Huang, Ai-hua, Zhou, Fei, Gan, Yi, Zhang, Yan-hua, Ma, Li
• Format: Journal Article
• Language: English
• Published: Hangzhou Zhejiang University Press 2020; Springer Nature B.V
• Subjects: Adenocarcinoma; AKT protein; Apoptosis; Biomedical and Life Sciences; Biomedicine; Cell cycle; Cell growth; Cell proliferation; Cytotoxicity; Environmental stress; Flow cytometry; FOXO3 protein; Gadd45A protein; Gene expression; Inhibitors; Kinases; Lung cancer; Lungs; Neoplasia; Proteasome inhibitors; Solid tumors; Targeted cancer therapy; Toxicity; Tumors; Up-regulation; R734.2; Carfilzomib; Cell cycle arrest; 细胞周期阻滞; Gadd45a; Lung adenocarcinoma; 卡非佐米 (Carfilzomib); 凋亡; Apoptosis; 肺腺癌; Carfilzomib; Lung adenocarcinoma; Gadd45a; Cell cycle arrest; Apoptosis
• ISSN: 1673-1581; 1862-1783
• DOI: 10.1631/jzus.B1900551

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.