Elevated iNOS and 3'-nitrotyrosine in Kaposi's Sarcoma tumors and mouse model.

Abstract

Kaposi's Sarcoma (KS) is a heterogenous, multifocal vascular malignancy caused by the human herpesvirus 8 (HHV8), also known as Kaposi's Sarcoma-Associated Herpesvirus (KSHV). Here, we show that KS lesions express iNOS/NOS2 broadly throughout KS lesions, with enrichment in LANA positive spindle cells. The iNOS byproduct 3-nitrotyrosine is also enriched in LANA positive tumor cells and colocalizes with a fraction of LANA-nuclear bodies. We show that iNOS is highly expressed in the L1T3/mSLK tumor model of KS. iNOS expression correlated with KSHV lytic cycle gene expression, which was elevated in late-stage tumors (>4 weeks) but to a lesser degree in early stage (1 week) xenografts. Further, we show that L1T3/mSLK tumor growth is sensitive to an inhibitor of nitric oxide, L-NMMA. L-NMMA treatment reduced KSHV gene expression and perturbed cellular gene pathways relating to oxidative phosphorylation and mitochondrial dysfunction. These finding suggest that iNOS is expressed in KSHV infected endothelial-transformed tumor cells in KS, that iNOS expression depends on tumor microenvironment stress conditions, and that iNOS enzymatic activity contributes to KS tumor growth.

• Authors: Olga Vladimirova, Samantha Soldan, Chenhe Su, Andrew Kossenkov, Owen Ngalamika, For Yue Tso, John T West, Charles Wood, Paul M Lieberman
• Journal: Tumour virus research (Tumour Virus Res) Vol. 15 Pg. 200259 (06 2023) ISSN: 2666-6790 [Electronic] Netherlands
• PMID: 36863485 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• 3-nitrotyrosine
• Antigens, Viral
• omega-N-Methylarginine
• NOS2 protein, human
• Nos2 protein, mouse

Topics

• Animals
• Humans
• Mice
• Antigens, Viral (genetics)
• Herpesvirus 8, Human (genetics)
• omega-N-Methylarginine
• Sarcoma, Kaposi (genetics)
• Tumor Microenvironment