<br>强效 USP10/13 拮抗剂 spautin-1 通过 ROS 介导的 DNA 损伤抑制黑色素瘤生长，并与顺铂具有协同作用。,Journal of Cellular and Molecular Medicine

当前位置： X-MOL 学术 › J. Cell. Mol. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

强效 USP10/13 拮抗剂 spautin-1 通过 ROS 介导的 DNA 损伤抑制黑色素瘤生长，并与顺铂具有协同作用。
Journal of Cellular and Molecular Medicine ( IF 4.3 ) Pub Date : 2020-03-04 , DOI: 10.1111/jcmm.15093
Jia Guo _{1,

2,

3} , JiangLing Zhang _{1,

2,

3} , Long Liang _{1,

2,

3,

4} , Nian Liu _{1,

2,

3} , Min Qi ₅ , Shuang Zhao _{1,

2,

3,

6} , Juan Su _{1,

2,

3,

6} , Jing Liu ₄ , Cong Peng _{1,

2,

3,

6} , Xiang Chen _{1,

2,

3,

6} , Hong Liu _{1,

2,

3,

6,

7}

Affiliation

恶性黑色素瘤是最具侵袭性的肿瘤之一。然而，有效的治疗策略有限，总体生存率仍然很低。通过利用转录组分析、组织阵列和分子生物学，我们发现两种关键的泛素特异性蛋白酶 (USP)：泛素特异性肽酶 10 (USP10) 和泛素特异性肽酶 10 (USP13) 在黑色素瘤中的 mRNA 和蛋白质显着升高。水平。 Spautin-1 已被报道为 USP10 和 USP13 拮抗剂，我们证明了 spautin-1 具有有效的抗肿瘤作用，如 MTS 和各种黑色素瘤细胞系中的集落形成测定所反映的，而在 HaCaT 和 JB6 细胞系中没有细胞毒性作用。从机制上讲，我们利用转录组学、qRT-PCR 验证、流式细胞术、蛋白质印迹和免疫荧光染色，确定细胞凋亡和 ROS 介导的 DNA 损伤是 spautin-1 介导的抗肿瘤作用的关键机制。重要的是，通过用靶向药物或化疗药物筛选spautin-1，我们发现spautin-1在黑色素瘤的治疗中与顺铂表现出协同作用。临床前，我们证明了 spautin-1 在细胞系来源的异种移植小鼠模型中显着减弱肿瘤生长，并且通过与顺铂联合治疗进一步增强其抗肿瘤作用。总而言之，我们的研究揭示了 spautin-1 作用于黑色素瘤的新分子机制，并确定了治疗黑色素瘤患者的潜在治疗策略。

"点击查看英文标题和摘要"

Potent USP10/13 antagonist spautin-1 suppresses melanoma growth via ROS-mediated DNA damage and exhibits synergy with cisplatin.

Malignant melanoma is one of the most invasive tumours. However, effective therapeutic strategies are limited, and overall survival rates remain low. By utilizing transcriptomic profiling, tissue array and molecular biology, we revealed that two key ubiquitin-specific proteases (USPs), ubiquitin-specific peptidase10 (USP10) and ubiquitin-specific peptidase10 (USP13), were significantly elevated in melanoma at the mRNA and protein levels. Spautin-1 has been reported as a USP10 and USP13 antagonist, and we demonstrated that spautin-1 has potent anti-tumour effects as reflected by MTS and the colony formation assays in various melanoma cell lines without cytotoxic effects in HaCaT and JB6 cell lines. Mechanistically, we identified apoptosis and ROS-mediated DNA damage as critical mechanisms underlying the spautin-1-mediated anti-tumour effect by utilizing transcriptomics, qRT-PCR validation, flow cytometry, Western blotting and immunofluorescence staining. Importantly, by screening spautin-1 with targeted or chemotherapeutic drugs, we showed that spautin-1 exhibited synergy with cisplatin in the treatment of melanoma. Pre-clinically, we demonstrated that spautin-1 significantly attenuated tumour growth in a cell line-derived xenograft mouse model, and its anti-tumour effect was further enhanced by cotreatment with cisplatin. Taken together, our study revealed a novel molecular mechanism of spautin-1 effecting in melanoma and identified a potential therapeutic strategy in treatment of melanoma patients.

更新日期：2020-04-22

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南