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GLS1 depletion inhibited colorectal cancer proliferation and migration via redox/Nrf2/autophagy-dependent pathway
Archives of Biochemistry and Biophysics ( IF 3.8 ) Pub Date : 2021-06-11 , DOI: 10.1016/j.abb.2021.108964
Hui-Yun Liu 1 , Hong-Sheng Zhang 1 , Min-Yao Liu 1 , Hong-Ming Li 1 , Xin-Yu Wang 1 , Miao Wang 1
Affiliation  

Cancer cells can metabolize glutamine to replenish TCA cycle intermediates for cell survival. Glutaminase (GLS1) is over-expressed in multiple cancers, including colorectal cancer (CRC). However, the role of GLS1 in colorectal cancer development has not yet fully elucidated. In this study, we found that GLS1 levels were significantly increased in CRC cells. Knockdown of GLS1 by shRNAs as well as GLS1 inhibitor BPTES decreased DLD1 and SW480 cell proliferation, colony formation and migration. Knockdown of GLS1 as well as BPTES induced reactive oxygen species (ROS) production, down-regulation of GSH/GSSG ratio, an decrease in Nrf2 protein expression and an increase in cytoplasmic Nrf2 protein expression in DLD1 and SW480 cells. Furthermore, Knockdown of GLS1 as well as BPTES inhibited autophagy pathway, antioxidant NAC and Nrf2 activator could reversed inhibition of GLS1-mediated an decrease in autophagic flux in DLD1 and SW480 cells. Depletion of GLS1-induced inhibition of DLD1 and SW480 CRC cell proliferation, colony formation and migration was reversed by autophagy inducer rapamycin. These results suggest that targeting GLS1 might be a new potential therapeutic target for the treatment of CRC.



中文翻译:


GLS1耗竭通过氧化还原/Nrf2/自噬依赖性途径抑制结直肠癌增殖和迁移



癌细胞可以代谢谷氨酰胺来补充 TCA 循环中间体以维持细胞生存。谷氨酰胺酶 (GLS1) 在多种癌症中过度表达,包括结直肠癌 (CRC)。然而,GLS1在结直肠癌发展中的作用尚未完全阐明。在这项研究中,我们发现 CRC 细胞中 GLS1 水平显着升高。 shRNA 以及 GLS1 抑制剂 BPTES 敲低 GLS1 可减少 DLD1 和 SW480 细胞增殖、集落形成和迁移。在 DLD1 和 SW480 细胞中,GLS1 和 BPTES 的敲除诱导活性氧 (ROS) 产生、GSH/GSSG 比率下调、Nrf2 蛋白表达减少以及细胞质 Nrf2 蛋白表达增加。此外,GLS1 和 BPTES 的敲低会抑制自噬途径,抗氧化剂 NAC 和 Nrf2 激活剂可以逆转 DLD1 和 SW480 细胞中 GLS1 介导的自噬流减少的抑制。自噬诱导剂雷帕霉素可逆转 GLS1 诱导的 DLD1 和 SW480 CRC 细胞增殖、集落形成和迁移的抑制作用。这些结果表明,靶向 GLS1 可能是治疗 CRC 的新的潜在治疗靶点。

更新日期:2021-06-15
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