Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression
Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression
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卡非佐米通过上调 Gadd45a 表达抑制肺腺癌的生长
DOI：
10.1631/jzus.b1900551
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发表时间：
2019-12
期刊：
影响因子：
--
通讯作者：
Ma Li
中科院分区：
文献类型：
--
作者：
Yang Fang;Liu Wang-wang;Chen Hui;Zhu Jia;Huang Ai-hua;Zhou Fei;Gan Yi;Zhang Yan-hua;Ma Li
蛋白酶体抑制剂在治疗血液肿瘤方面取得了显着的成功。将这些药物应用于实体瘤治疗受到了广泛关注。最近的临床前研究表明，第二代蛋白酶体抑制剂卡非佐米（CFZ）能够有效抑制肺腺癌的细胞增殖。然而，尚未获得有关该机制的见解。在本研究中，我们系统地研究了CFZ在肺腺癌细胞增殖和生长、细胞周期停滞和凋亡中的功能。流式细胞术实验表明CFZ显着诱导肺腺癌G2/M细胞周期停滞和细胞凋亡。 MTS 和集落形成测定表明，CFZ 显着抑制肺腺癌细胞的存活。所有结果均与 Gadd45a 表达上调相关，Gadd45a 是调节细胞周期停滞和细胞凋亡以响应生理和环境应激的重要基因。此处，CFZ 处理后观察到 Gadd45a 表达上调。敲除 Gadd45a 表达可抑制 CFZ 处理的细胞中 G2/M 期停滞和细胞凋亡，并降低该药物的细胞毒性。蛋白表达分析进一步确定AKT/FOXO3a通路参与CFZ处理后Gadd45a的上调。这些发现揭示了蛋白酶体抑制剂抗实体瘤活性的新机制，并为肺腺癌的新的优选治疗策略提供了线索。我们相信，Gadd45a 表达可以成为评估蛋白酶体抑制剂在实体瘤治疗中疗效的高度有前景的候选预测因子。
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.
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干扰素 - 通过乳腺上皮细胞中的 c-Abl/HDAC2 信号通路调节细胞恶性生长
DOI：
10.1631/jzus.b1800211
发表时间：
2019
期刊：
Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)
影响因子：
--
作者：
Ren Wen bo;Xia Xiao jing;Huang Jing;Guo Wen fei;Che Yan yi;Huang Ting hao;Lei Lian cheng
通讯作者：
Lei Lian cheng
影响因子：
30.8
作者：
Hollander, MC;Sheikh, MS;Fornace, AJ
通讯作者：
Fornace, AJ
影响因子：
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作者：
Chung, HK;Yi, YW;Shong, MH
通讯作者：
Shong, MH
FOXO3a 在致癌过程中的关键作用
影响因子：
37.3
作者：
Liu Y;Ao X;Ding W;Ponnusamy M;Wu W;Hao X;Yu W;Wang Y;Li P;Wang J
通讯作者：
Wang J
DOI：
10.1186/s13046-014-0111-8
发表时间：
2014-12-31
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Baker AF;Hanke NT;Sands BJ;Carbajal L;Anderl JL;Garland LL
通讯作者：
Garland LL