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

Abstract

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.

• Authors: Jia Guo, JiangLing Zhang, Long Liang, Nian Liu, Min Qi, Shuang Zhao, Juan Su, Jing Liu, Cong Peng, Xiang Chen, Hong Liu
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 24 Issue 7 Pg. 4324-4340 (04 2020) ISSN: 1582-4934 [Electronic] England
• PMID: 32129945 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Antineoplastic Agents
• Benzylamines
• Quinazolines
• Reactive Oxygen Species
• USP10 protein, human
• spautin-1
• USP13 protein, human
• Ubiquitin Thiolesterase
• Ubiquitin-Specific Proteases
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzylamines (pharmacology)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• DNA Damage (drug effects)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Melanoma (drug therapy, genetics, pathology)
• Mice
• Quinazolines (pharmacology)
• Reactive Oxygen Species
• Skin Neoplasms (drug therapy, genetics, pathology)
• Ubiquitin Thiolesterase (genetics)
• Ubiquitin-Specific Proteases (genetics)
• Xenograft Model Antitumor Assays
• Melanoma, Cutaneous Malignant