Cold atmospheric plasmas target breast cancer stemness via modulating AQP3-19Y mediated AQP3-5K and FOXO1 K48-ubiquitination.
Cold atmospheric plasmas target breast cancer stemness via modulating AQP3-19Y mediated AQP3-5K and FOXO1 K48-ubiquitination.
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DOI：
10.7150/ijbs.72296
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发表时间：
2022
影响因子：
9.2
通讯作者：
Thompson, Erik
中科院分区：
文献类型：
--
作者：
Dai, Xiaofeng;Cai, Dongyan;Wang, Peiyu;Nan, Nan;Yu, Lihui;Zhang, Zhifa;Zhou, Renwu;Hua, Dong;Zhang, Jianying;Ostrikov, Kostya (Ken);Thompson, Erik
关键词：
冷大气等离子体(CAP)对多种癌症具有选择性，副作用小，但其分子机制尚不清楚。通过对整个转录组进行测序，然后进行体外、体内和临床样本的分析，我们认为CAP是一种通过AQP3/FOXO1轴靶向肿瘤干细胞的有前景的肿瘤治疗方法。帽生成的活性物种通过AQP3穿透细胞，并抑制RPS6KA3，RPS6KA3是AQP3和FOXO1的共同激酶。减少的AQP3-19Y磷酸化抑制了SCAF11介导的AQP3-5K K48-泛素化，从而破坏了FOXO1的稳定性。抑制FOXO1的磷酸化抑制了其在维持肿瘤干性方面的调节活性，包括ALDH1和IL6。CAP与阿托伐他汀联用，体内外抗癌效果明显增强。我们建议CAP作为一种针对癌症干的“选择性”肿瘤治疗，AQP3/FOXO1轴是一个分子机制。我们报道了SCAF11是AQP3和FOXO1的E3泛素连接酶，AQP3-5K是AQP3 K48-泛素化位点，并强调了AQP3-19Y在这一过程中的重要作用。我们通过将阿托伐他汀与CAP协同以提高疗效，将其重新定位到肿瘤治疗组合中。我们预计CAP在针对高干细胞的恶性肿瘤方面的疗效，或作为一种辅助治疗最终治愈癌症的希望。
Cold atmospheric plasma (CAP) is selective against many cancers with little side effect, yet its molecular mechanism remains unclear. Through whole transcriptome sequencing followed by assays in vitro, in vivo and using clinical samples, we propose CAP as a promising onco-therapy targeting cancer stemness via the AQP3/FOXO1 axis. CAP-generated reactive species penetrated cells via AQP3 and suppressed RPS6KA3, a shared kinase of AQP3 and FOXO1. Reduced AQP3-19Y phosphorylation suppressed SCAF11-mediated AQP3-5K K48-ubiquitination that led to sabotaged FOXO1 stability. Inhibited FOXO1 phosphorylation retarded its regulatory activities in maintaining cancer stemness including ALDH1 and IL6. Enhanced anti-cancer efficacy was observed through combining CAP with Atorvastatin in vitro and in vivo. We propose CAP as a 'selective' onco-therapeutic against cancer stemness, with the AQP3/FOXO1 axis being one molecular mechanism. We report SCAF11 as an E3 ubiquitin ligase of both AQP3 and FOXO1, identify AQP3-5K as an AQP3 K48-ubiquitination site, and emphasize the essential role of AQP3-19Y in this process. We reposition Atorvastatin into the onco-therapeutic portfolio by synergizing it with CAP towards enhanced efficacy. We anticipate the efficacy of CAP in targeting malignancies of high stemness alone or as an adjuvant therapy towards the hope of ultimate cancer cure.
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DOI：
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发表时间：
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期刊：
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影响因子：
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