Inhibition of Heme Oxygenase-1 Interferes with the Transforming Activity of the Kaposi Sarcoma Herpesvirusencoded G Protein-coupled Receptor

MARINISSEN, M. J.; TANOS, T.; BOLOS, M.; DE SAGARRA, M. R.; COSO, O. A.; CUADRADO, A.

JOURNAL OF BIOLOGICAL CHEMISTRY

Año: 2006 p. 11332 - 11345

0021-9258

AbstractHeme oxygenase-1 (HO-1), the inducible enzyme responsible forthe rate-limiting step in the heme catabolism, is expressed in AIDSKaposisarcoma (KS) lesions. Its expression is up-regulated by theKaposi sarcoma-associated herpesvirus (KSHV) in endothelial cells,but the mechanisms underlying KSHV-induced HO-1 expression arestill unknown. In this study we investigated whether the oncogenic Gprotein-coupled receptor (KSHV-GPCR or vGPCR), one of the keyKSHV genes involved in KS development, activated HO-1 expression.Here we show that vGPCR induces HO-1 mRNA and protein levels infibroblasts and endothelial cells. Moreover, targeted knock-down geneexpression of HO-1 by small hairpin RNA and chemical inhibition ofHO-1 enzymatic activity by tin protoporphyrin IX (SnPP), impairedvGPCR-induced survival, proliferation, transformation, and vascularendothelial growth factor (VEGF)-A expression. vGPCR-expressingcells implanted in the dorsal flank of nude mice developed tumors withelevated HO-1 expression and activity. Chronic administration ofSnPP to the implanted mice, under conditions that effectively blockedHO-1 activity and VEGF-A expression in the transplanted cells, strikinglyreducedtumorgrowth,withoutapparentsideeffects.Onthecontrary,administration of the HO-1 inducer cobalt protoporphyrin(CoPP) further enhanced vGPCR-induced tumor growth. These datapostulate HO-1 as an important mediator of vGPCR-induced tumorgrowth and suggest that inhibition of intratumoral HO-1 activity bySnPP may be a potential therapeutic strategy.