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M512199200v1
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Papers In Press, published online ahead of print February 13, 2006
J. Biol. Chem, 10.1074/jbc.M512199200
Submitted on November 14, 2005
Accepted on February 13, 2006

Inhibition of heme oxygenase-1 interferes with the transforming activity of the Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor

Maria Julia Marinissen, Tamara T. Tanos, Marta Bolós, Maria Rosa de Sagarra, Omar A. Coso, and Antonio Cuadrado

Instituto de Investigaciones Biomédicas A. Sols UAM-CSIC, Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Madrid 28029

Corresponding Author: mjmarinissen{at}iib.uam.es

Heme oxygenase-1 (HO-1), the inducible enzyme responsible for the rate-limiting step in the heme catabolism, is expressed in AIDS-Kaposi’s sarcoma (KS) lesions. Its expression is upregulated by the Kaposi’s 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 shRNA and chemical inhibition of HO-1 enzymatic activity by Sn protoporphyrin IX (SnPP), impaired vGPCR-induced survival, proliferation, transformation, and 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 Co 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.


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