A Role for Virally Induced Reactive Oxygen Species in Kaposi's Sarcoma Herpesvirus Tumorigenesis

Abstract

Aims: Kaposi's sarcoma (KS), caused by the Kaposi's sarcoma herpesvirus (KSHV), is an AIDS-associated cancer characterized by angiogenesis and proliferation of spindle cells. Rac1-activated reactive oxygen species (ROS) production has been implicated in KS tumorigenesis. We used an animal model of KSHV-induced Kaposi's sarcomagenesis (mECK36) to study the role of ROS in KS and the efficacy of N-acetyl l-cysteine (NAC) in inhibiting or preventing KS. Results: Signaling by the KSHV early lytic gene viral G protein-coupled receptor (vGPCR) activated ROS production in mECK36 cells via a Rac1-NADPH oxidase pathway. Induction of the lytic cycle in KSHV-infected KS spindle cells upregulated ROS along with upregulation of vGPCR expression. We also found that expression of the major latent transcript in 293 cells increased ROS levels. ROS scavenging with NAC halted mECK36 tumor growth in a KSHV-specific manner. NAC inhibited KSHV latent gene expression as well as tumor angiogenesis and lymphangiogenesis. These effects correlated with the reduction of vascular endothelial growth factor (VEGF), c-myc, and cyclin D1, and could be explained on the basis of inhibition of STAT3 tyrosine phosphorylation. NAC prevented mECK36 de novo tumor formation. Molecular analysis of NAC-resistant tumors revealed a strong upregulation of Rac1 and p40 PHOX. Innovation and Conclusion: Our results demonstrate that ROS-induction by KSHV plays a causal role in KS oncogenesis by promoting proliferation and angiogenesis. Our results show that both ROS and their molecular sources can be targeted therapeutically using NAC or other Food and Drug Administration (FDA)approved inhibitors for prevention and treatment of AIDS-KS. Antioxid. Redox Signal. 18, 80-90.

Modulation of host ROS metabolism is essential for viral infection of a bloom-forming coccolithophore in the ocean

“…U Sheyn et al virus, hepatitis C virus and HIV (Perl and Banki, 2000;Ye et al, 2011;Bottero et al, 2013;Ma et al, 2013). On the other hand, in plants, during tobacco mosaic virus infection, ROS signaling was found to initiate plant defense hypersensitive response (Allan et al, 2001;Yoda et al, 2003;Love et al, 2005).…”

Reactive Oxygen Species Are Induced by Kaposi's Sarcoma-Associated Herpesvirus Early during Primary Infection of Endothelial Cells To Promote Virus Entry

“…Inhibition of ROS by the antioxidant N-acetylcysteine (NAC) has also been shown to prevent KSHV tumorigenesis (6,8). In a PEL mouse model, NAC-treated animals had an extended life span relative to the control group (6).…”

“…In a PEL mouse model, NAC-treated animals had an extended life span relative to the control group (6). In addition, NAC reduced the tumor size in an endothelial KS-mouse model by inhibiting the expression of both viral and cellular genes involved in proliferation and angiogenesis (8). In all these studies, the role of ROS has been elucidated only in endothelial or B-cell latency models.…”

Multivariate discriminant analysis of redox and progression indexes in Cuban AIDS patients with Kaposis sarcoma

“…In vitro studies conducted by Ye et al showed that AIDS-KS strains demonstrate enhanced susceptibility to oxidative stress as induced by either physiologically relevant levels of hydrogen peroxide [18] or conducted by Li et al who show activation through a drug capable of undergoing redox cycling (doxorubicin) [19]. AIDS-KS cells also show an acute hyperresponsiveness to a pro-inflammatory cytokine that signals by redox-mediated pathways (interleukin 6) [20] and possess an inherent perturbation in their thiol redox status characterized by significantly lower levels of both glutathione (GSH) and the GSH reductase co-factor, nicotinamide adenine dinucleotide phosphate [21].…”

“…The better comprehension about the interrelation of viral and host factors in KS carcinogenesis is necessary for the rational development of interdisciplinary clinical interpretation and effective intervention [1,21,22]. The aim of this study was to determine the redox status in AIDS-KS individuals.…”