The small GTPase RhoA links the Kaposi sarcoma-associated herpes

MARIA JOSE MARTIN; TAMARA B. TANOS; ANA BELEN GARCIA; DANIEL MARTIN; J. SILVIO GUTKIND; OMAR A. COSO; MARIA J. MARINISSEN

Cracovia Polonia

Congreso; Heme Oxygenases 2007 The 5th International Congress; 2007

Jagiellonian University

Heme oxygenase-1 (HO-1), an inducible enzyme that metabolizes the heme group, is highlyexpressed in human Kaposi Sarcoma lesions. Its expression is upregulated by the G proteincoupledreceptor from the Kaposi sarcoma-associated herpes virus (vGPCR). Althoughrecent evidence shows that HO-1 contributes to vGPCR-induced tumorigenesis and vascularendothelial growth factor (VEGF) expression, the molecular steps that link vGPCR to HO-1remain unknown. Here we show that vGPCR induces HO-1 expression and transformationthrough the G13 subunit of heterotrimeric G proteins and the small GTPase RhoA. vGPCRinduces RhoA activity and uncoupling signal transmission from G13 to RhoA or inhibition ofRhoA impairs vGPCR-induced ho-1 promoter activity. Moreover, shRNA mediated knockdownexpression of RhoA reduces vGPCR-induced VEFG-A secretion and blocks tumorgrowth in a murine allograft tumor model. NIH-3T3 cells expressing constitutively activatedG13 or RhoA implanted in nude mice develop tumors displaying spindle-shaped cells thatexpress HO-1 and VEGF-A, similarly to vGPCR-derived tumors. RhoAQL-induced tumorgrowth is reduced 80% by shRNA mediated knock-down expression of HO-1 in the implantedcells. Likewise, inhibition of HO-1 activity by chronic administration of the HO-1 inhibitorSn protoporphyrin IX (SnPP) to mice reduces RhoAQL-induced tumor growth by 70%. Ourstudy shows that vGPCR induces HO-1 expression through the G13/RhoA axes and uncoversa role for HO-1 as a potential therapeutic target in tumors where RhoA has oncogenicactivity.