Arginase‐II promotes melanoma migration and adhesion through enhancing hydrogen peroxide production and STAT3 signaling

• Published in: Journal of cellular physiology Vol. 235; no. 12; pp. 9997 - 10011
• Main Authors: Yu, Yi, Ladeiras, Diogo, Xiong, Yuyan, Boligan, Kayluz Frias, Liang, Xiujie, Gunten, Stephan, Hunger, Robert E., Ming, Xiu‐Fen, Yang, Zhihong
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.12.2020
• Subjects: Adhesion; Animals; Arginase; Arginase - antagonists & inhibitors; Arginase - genetics; arginase‐II; Catalase; Cell adhesion & migration; Cell Adhesion - drug effects; Cell death; Cell growth; Cell Line, Tumor; Cell lines; Cell migration; Cell Movement - drug effects; Cell number; Cell proliferation; Cell Proliferation - drug effects; Endothelial cells; Endothelial Cells - drug effects; Enzymatic activity; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Humans; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Inhibitors; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Metastases; Metastasis; Mitochondria; Molecular modelling; Polyamines; ROS; Signal Transduction - drug effects; STAT3; Stat3 protein; STAT3 Transcription Factor - genetics; Superoxide dismutase; Tumors; melanoma; arginase-II; metastasis; ROS; STAT3
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29814

Elevated arginase type II (Arg‐II) associates with higher grade tumors. Its function and underlying molecular mechanisms in melanoma remain elusive. In the present study, we observed a significantly higher frequency of Arg‐II expression in melanoma of patients with metastasis than those without metastasis. Silencing Arg‐II in two human melanoma cell lines slowed down the cell growth, while overexpression of native but not a catalytically inactive Arg‐II promoted cell proliferation without affecting cell death. Treatment of cells with arginase inhibitor also reduced melanoma cell number, demonstrating that Arg‐II promotes melanoma cell proliferation dependently of its enzymatic activity. However, results from silencing Arg‐II or overexpressing native or the inactive Arg‐II as well as treatment with arginase inhibitor showed that Arg‐II promotes melanoma metastasis‐related processes, such as melanoma cell migration and adhesion on endothelial cells, independently of its enzymatic activity. Moreover, the treatment of the cells with STAT3 inhibitor suppressed Arg‐II‐promoted melanoma cell migration and adhesion. Furthermore, catalase, but not superoxide dismutase, prevented STAT3 activation as well as increased melanoma cell migration and adhesion induced by overexpressing native or the inactive Arg‐II. Taken together, our study uncovers both activity‐dependent and independent mechanisms of Arg‐II in promoting melanoma progression. While Arg‐II enhances melanoma cell proliferation through polyamine dependently of its enzymatic activity, it promotes metastasis‐related processes, that is, migration and adhesion onto endothelial cell, through mitochondrial H2O2‐STAT3 pathway independently of the enzymatic activity. Suppressing Arg‐II expression rather than inhibiting its enzymatic activity may, therefore, represent a novel strategy for the treatment of melanoma. Arginase type II (Arg‐II) promotes melanoma cell proliferation dependently of its enzymatic activity, while promotes metastasis‐related migration and adhesion to endothelial cells through H2O2‐STAT3 pathway independently of the enzymatic activity. Suppressing Arg‐II expression rather than inhibiting its enzymatic activity may represent a novel strategy for the treatment of melanoma.