Effects of 2-(2-Chlorophenyl)ethylbiguanide on ERAD Component Expression in HT-29 Cells Under a Serum- and Glucose-Deprived Condition
Effects of 2-(2-Chlorophenyl)ethylbiguanide on ERAD Component Expression in HT-29 Cells Under a Serum- and Glucose-Deprived Condition
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DOI：
10.1007/s12010-019-02969-4
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发表时间：
2019-08-01
影响因子：
3
通讯作者：
Nagasawa, Hideko
中科院分区：
文献类型：
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作者：
Oh-hashi, Kentaro;Matsumoto, Shiori;Nagasawa, Hideko
最近，我们的特点是一种新的phenylamine衍生物，2-（2-氯苯基）乙基双胍（2-Cl-Phen），HT-29细胞的细胞毒性作用下的血清和葡萄糖剥夺的条件下，发现2-Cl-Phen衰减ATF 4和GRP 78，典型的下游目标的未折叠蛋白反应（UPR），连同c-Myc蛋白的表达在转录和转录后的方式。在目前的研究中，我们专注于表达ER相关蛋白降解（ERAD）组件治疗后，与2-氯-Phen下的血清和葡萄糖剥夺条件。在9个ER定位因子调节ER内的蛋白质质量控制，Herp，GRP 78，GRP 94和OS 9蛋白质的量显着下调2-Cl-Phen治疗。特别是，更换培养基与血清和葡萄糖剥夺培养基诱导的Herp蛋白的表达在早期阶段。Herp蛋白的这种增加伴随着其mRNA的增加，并且其诱导被2-Cl-Phen显著抑制。然而，与蛋白酶体抑制剂，MG 132，共治疗恢复Herp的表达仅在有限的程度上。总之，这些结果表明，2-Cl-Phen改变了几个ERAD组件的表达，特别是通过转录抑制Herp诱导2-Cl-Phen时，它发生在早期阶段，这一发现提供了新的见解理解2-Cl-Phen介导的细胞毒性的机制。
We recently characterized the cytotoxic action of a novel phenformin derivative, 2-(2-chlorophenyl)ethylbiguanide (2-Cl-Phen), on HT-29 cells under a serum- and glucose-deprived condition and found that 2-Cl-Phen attenuated ATF4 and GRP78, typical downstream targets of the unfolded protein response (UPR), together with c-Myc protein expression in a transcriptional and posttranscriptional manner. In the current study, we focused on the expression of ER-associated protein degradation (ERAD) components after treatment with 2-Cl-Phen under a serum- and glucose-deprived condition. Among nine ER-localizing factors regulating protein quality control within the ER, the amounts of Herp, GRP78, GRP94, and OS9 proteins were significantly downregulated by treatment with 2-Cl-Phen. In particular, replacement of the culture medium with the serum- and glucose-deprived medium induced the expression of Herp protein at the early phase. This increase in Herp protein was accompanied by an increase in its mRNA, and its induction was significantly dampened by 2-Cl-Phen. However, cotreatment with a proteasome inhibitor, MG132, restored Herp expression only to a limited extent. Taken together, these results show that 2-Cl-Phen changed the expression of several ERAD components, especially by transcriptional inhibition of Herp induction by 2-Cl-Phen when it occurred at an early phase, and this finding provides new insights into understanding the mechanisms of 2-Cl-Phen-mediated cytotoxicity.