Uev1A通过AKT-FOXO1-BIM信号通路促进乳腺癌细胞存活和化疗耐药。

Uev1A promotes breast cancer cell survival and chemoresistance through the AKT-FOXO1-BIM pathway.

作者信息

Wu Zhaojia, Niu Tong, Xiao Wei

机构信息

1Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5 Canada.

2College of Life Sciences, Capital Normal University, Beijing, 100048 China.

出版信息

Cancer Cell Int. 2019 Dec 9;19:331. doi: 10.1186/s12935-019-1050-4. eCollection 2019.

BACKGROUND

Ubiquitin-conjugating enzyme variant is required for Ubc13-catalyzed K63-linked poly-ubiquitination that regulates several signaling pathways including NF-κB, MAPK and PI3K/AKT. Previous reports implicate as a potential proto-oncogene and have shown that promotes breast cancer metastasis through constitutive NF-кB activation. Ubc13-Uev1A along with TARF6 can also ubiquitinate AKT but its downstream events are unclear.

METHODS

In this study, we experimentally manipulated expression in two typical breast cancer cell lines MDA-MB-231 and MCF7 under serum starvation conditions and monitored AKT activation and its downstream protein levels, as well as cellular sensitivity to chemotherapeutic agents.

RESULTS

We found that overexpression of is sufficient to activate the AKT signaling pathway that in turn inhibits and expression to promote cell survival under serum starvation conditions and enhances cellular resistance to chemotherapy. Consistently, experimental depletion of Uev1 in breast cancer cells inhibits AKT signaling and promotes FOXO1 and BIM expression to reduce cell survival under serum starvation stress and enhance chemosensitivity.

CONCLUSIONS

Uev1A promotes cell survival under serum starvation stress through the AKT-FOXO1-BIM axis in breast cancer cells, which unveals a potential therapeutic target in the treatment of breast cancers.

背景

泛素结合酶变体（Uev1A）是Ubc13催化的K63连接的多聚泛素化所必需的，该过程调节包括NF-κB、丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/AKT）在内的多种信号通路。先前的报道表明Uev1A是一种潜在的原癌基因，并已显示其通过组成型NF-κB激活促进乳腺癌转移。Ubc13-Uev1A与肿瘤坏死因子受体相关因子6（TRAF6）一起也能使AKT泛素化，但其下游事件尚不清楚。

方法

在本研究中，我们在血清饥饿条件下通过实验操纵两种典型乳腺癌细胞系MDA-MB-231和MCF7中的Uev1A表达，并监测AKT激活及其下游蛋白水平，以及细胞对化疗药物的敏感性。

结果

我们发现Uev1A的过表达足以激活AKT信号通路，进而抑制叉头框蛋白O1（FOXO1）和Bim凋亡蛋白（BIM）的表达，以促进血清饥饿条件下的细胞存活，并增强细胞对化疗的抗性。一致地，乳腺癌细胞中Uev1的实验性缺失抑制AKT信号传导，促进FOXO1和BIM表达，以降低血清饥饿应激下的细胞存活并增强化学敏感性。