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J. Biol. Chem., Vol. 281, Issue 16, 11332-11346, April 21, 2006

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

Maria Julia Marinissen¹, Tamara Tanos², Marta Bolós, Maria Rosa de Sagarra, Omar A. Coso, and Antonio Cuadrado

From the Instituto de Investigaciones Biomédicas A. Sols Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid 28029, Spain and the Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Instituto de Fisiologia, Biologia Molecular and Neurociencias-Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires, Argentina

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.

Received for publication, November 14, 2005 , and in revised form, February 1, 2006.

^* This work was supported in part by grants from Fundación Médica Mutua Madrileña (Spain), Grant SAF2005-03020 from Ministerio de Educación y Ciencia (Spain), Centro de Estudios de América Latina (Universidad Autónoma de Madrid-Banco Santander, Spain) and RSMN (03/08) from the Health Institute Carlos III. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

² Recipient of European Molecular Biology Organization and International Union against Cancer International Cancer Technology Transfer fellowships during periods spent at the laboratory in Spain.

¹ To whom correspondence should be addressed: Inst. de Investigaciones Biomédicas A. Sols UAM-CSIC, Dept. de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Laboratorio C-11, Arzobispo Morcillo 4, Madrid 28029, Spain. Tel.: 34-91-497-5464; Fax: 34-91-576-7442; E-mail: mjmarinissen{at}iib.uam.es.

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