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EPS8 supports pancreatic cancer growth by inhibiting BMI1 mediated proteasomal degradation of ALDH7A1
Experimental Cell Research ( IF 3.7 ) Pub Date : 2021-08-13 , DOI: 10.1016/j.yexcr.2021.112782
Mingzhu Tan 1 , Jun Meng 2 , Xiaojuan Sun 2 , Xiaowei Fu 3 , Ruihao Wang 1
Affiliation  

Aldehyde dehydrogenase 7 family member A1 (ALDH7A1) is an enzyme catalyzing lipid peroxidation of fatty aldehydes. It plays a critical role in sustaining high oxygen consumption rate (OCR) and ATP production in pancreatic ductal adenocarcinoma (PADC). However, why PADC cells maintain a relatively high level of ALDH7A1 concentration is still not well understood. In the current study, we explored the interplay between epidermal growth factor receptor kinase substrate 8 (EPS8) and ALDH7A1 in PADC cells. PADC cell lines MIA PaCa-2 and AsPANC-1 were used for in vitro and in vivo studies. The co-IP assay showed mutual interactions between Flag-EPS8 and Myc-ALDH7A1 in both MIA PaCa-2 and AsPANC-1 cells. EPS8 knockdown resulted in decreased ALDH7A1 protein levels and increased poly-ubiquitination. An interaction was observed between ALDH7A1 and BMI1 but not between BMI1 and EPS8. BMI1 knockdown reduced ALDH7A1 poly-ubiquitination and degradation caused by EPS8 knockdown. Dual EPS8 and ALDH7A1 knockdown had a synergistic effect on suppressing PADC cell proliferation in vitro and in vivo. In conclusion, this study revealed that EPS8 supports PADC growth by interacting with ALDH7A1 and inhibiting BMI1 mediated proteasomal degradation of ALDH7A1.



中文翻译:

EPS8 通过抑制 BMI1 介导的 ALDH7A1 蛋白酶体降解来支持胰腺癌的生长

醛脱氢酶 7 家族成员 A1 (ALDH7A1) 是一种催化脂肪醛脂质过氧化的酶。它在维持胰腺导管腺癌 (PADC) 的高耗氧率 (OCR) 和 ATP 产生方面发挥着关键作用。然而,为什么 PADC 细胞保持较高水平的 ALDH7A1 浓度仍不清楚。在当前的研究中,我们探索了 PADC 细胞中表皮生长因子受体激酶底物 8 (EPS8) 和 ALDH7A1 之间的相互作用。PADC 细胞系 MIA PaCa-2 和 AsPANC-1 用于体外体内研究。co-IP 测定显示 Flag-EPS8 和 Myc-ALDH7A1 在 MIA PaCa-2 和 AsPANC-1 细胞中的相互作用。EPS8敲低导致 ALDH7A1 蛋白水平降低和多泛素化增加。在 ALDH7A1 和 BMI1 之间观察到相互作用,但在 BMI1 和 EPS8 之间没有观察到相互作用。BMI1敲低减少了由EPS8敲低引起的ALDH7A1多泛素化和降解。双EPS8ALDH7A1敲低在体外体内抑制PADC细胞增殖具有协同作用。总之,这项研究表明,EPS8 通过与 ALDH7A1 相互作用并抑制 BMI1 介导的 ALDH7A1 蛋白酶体降解来支持 PADC 生长。

更新日期:2021-08-24
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