Abstract
Heme oxygenase-1 (HO-1), the inducible enzyme responsible for the rate-limiting step in the heme catabolism, is expressed in AIDS-Kaposi sarcoma (KS) lesions. Its expression is up-regulated by the Kaposi sarcoma-associated herpesvirus (KSHV) in endothelial cells, but the mechanisms underlying KSHV-induced HO-1 expression are still unknown. In this study we investigated whether the oncogenic G protein-coupled receptor (KSHV-GPCR or vGPCR), one of the key KSHV genes involved in KS development, activated HO-1 expression. Here we show that vGPCR induces HO-1 mRNA and protein levels in fibroblasts and endothelial cells. Moreover, targeted knock-down gene expression of HO-1 by small hairpin RNA and chemical inhibition of HO-1 enzymatic activity by tin protoporphyrin IX (SnPP), impaired vGPCR-induced survival, proliferation, transformation, and vascular endothelial growth factor (VEGF)-A expression. vGPCR-expressing cells implanted in the dorsal flank of nude mice developed tumors with elevated HO-1 expression and activity. Chronic administration of SnPP to the implanted mice, under conditions that effectively blocked HO-1 activity and VEGF-A expression in the transplanted cells, strikingly reduced tumor growth, without apparent side effects. On the contrary, administration of the HO-1 inducer cobalt protoporphyrin (CoPP) further enhanced vGPCR-induced tumor growth. These data postulate HO-1 as an important mediator of vGPCR-induced tumor growth and suggest that inhibition of intratumoral HO-1 activity by SnPP may be a potential therapeutic strategy.
Highlights
Transient Expression of vGPCR from the Kaposi Sarcoma-associated Herpesvirus Induces ho-1 Promoter Activity and Heme oxygenase-1 (HO-1) Protein Expression—As one of the first observations of the transforming activity of vGPCR derived from its overexpression in NIH3T3 fibroblasts [16], we used this cell line to investigate whether the receptor was able to induce the transcriptional activity of a 15-kb murine ho-1 promoter
The effect of vGPCR on the ho-1 promoter activity was comparable with that of the receptor on the activity of a reporter gene driven by the vascular endothelial growth factor promoter, a known target DNA regulatory sequence for the viral receptor [16], which served as a control (Fig. 1B). vGPCR, unlike its cellular homologue CXCR2, has ligand-independent activity
Recent findings showing elevated expression levels of HO-1 in biopsies from tumors of Kaposi sarcoma (KS) patients [12] prompted us to investigate whether vGPCR, one of the key genes involved in the development of KS, was able to induce the constitutive expression of HO-1
Summary
The Kaposi sarcoma (KS) is the most frequent tumor in AIDS patients, characterized by multifocal angioproliferative lesions containing spindle cells derived from the infection of endothelial cells by the KSHV [13] This virus ( denominated human herpesvirus-8) is involved in all clinical forms of KS. Our data indicate that targeted knockdown gene expression of HO-1 and chemical inhibition of HO-1 enzymatic activity impaired vGPCR-induced VEGF expression, survival, proliferation, and transformation both in cell culture and in a murine allograft tumor model. These findings uncovered the identity of HO-1 as a potential therapeutic target in KS
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