Background Ubiquitin-conjugating enzyme variant UEV1A is required for Ubc13-catalyzed K63-linked poly-ubiquitination that regulates several signaling pathways including NF-κB, MAPK and PI3K/AKT. Previous reports implicate UEV1A as a potential proto-oncogene and have shown that UEV1A 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 UEV1 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 UEV1A is sufficient to activate the AKT signaling pathway that in turn inhibits FOXO1 and BIM 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.

中文翻译：

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

背景 泛素结合酶变体 UEV1A 是 Ubc13 催化的 K63 连接的多泛素化所必需的，该多泛素化调节包括 NF-κB、MAPK 和 PI3K/AKT 在内的多种信号通路。以前的报告暗示 UEV1A 是一种潜在的原癌基因，并表明 UEV1A 通过组成型 NF-кB 激活促进乳腺癌转移。Ubc13-Uev1A 和 TARF6 也可以泛素化 AKT，但其下游事件尚不清楚。方法 在这项研究中，我们在血清饥饿条件下实验性地操纵了两种典型乳腺癌细胞系 MDA-MB-231 和 MCF7 中 UEV1 的表达，并监测了 AKT 活化及其下游蛋白水平，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FOXO1和BIM的表达，从而促进血清饥饿条件下的细胞存活，增强细胞对化疗的抵抗力。一致地，乳腺癌细胞中 Uev1 的实验性消耗会抑制 AKT 信号传导并促进 FOXO1 和 BIM 表达，从而降低血清饥饿应激下的细胞存活率并增强化学敏感性。结论 Uev1A通过AKT-FOXO1-BIM轴促进乳腺癌细胞在血清饥饿应激下的细胞存活，揭示了乳腺癌治疗的潜在治疗靶点。乳腺癌细胞中 Uev1 的实验性消耗抑制 AKT 信号传导并促进 FOXO1 和 BIM 表达，以降低血清饥饿应激下的细胞存活率并增强化学敏感性。结论 Uev1A通过AKT-FOXO1-BIM轴促进乳腺癌细胞在血清饥饿应激下的细胞存活，揭示了乳腺癌治疗的潜在治疗靶点。乳腺癌细胞中 Uev1 的实验性消耗抑制 AKT 信号传导并促进 FOXO1 和 BIM 表达，以降低血清饥饿应激下的细胞存活率并增强化学敏感性。结论 Uev1A通过AKT-FOXO1-BIM轴促进乳腺癌细胞在血清饥饿应激下的细胞存活，揭示了乳腺癌治疗的潜在治疗靶点。