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 t...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.展开更多
基金Project supported by the National Natural Science Foundation of China(Nos.81601992,81802986,and 81601029)the Natural Science Foundation of Zhejiang Province(No.LQ16H160008)the Medical and Health Program of Zhejiang Province(No.2019338991),China
文摘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.
