The Galpha12/13 family of heterotrimeric G proteins and the small GTPase RhoA link the Kaposi sarcoma-associated herpes virus G protein-coupled receptor to heme oxygenase-1 expression and tumorigenesis.

MARTIN M. J.; TANOS T.; GARCIA A. B.; MARTIN D.; GUTKIND J. S.; COSO O. A.; MARINISSEN M. J.

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Año: 2007 p. 34510 - 34524

0021-9258

Heme oxygenase-1 (HO-1), an inducible enzyme that metabolizesthe heme group, is highly expressed in human Kaposi sarcomalesions. Its expression is up-regulated by the G proteincoupledreceptor from the Kaposi sarcoma-associated herpesvirus (vGPCR). Although recent evidence shows that HO-1 contributesto vGPCR-induced tumorigenesis and vascular endothelialgrowth factor (VEGF) expression, the molecular stepsthat link vGPCR to HO-1 remain unknown. Here we show thatvGPCR induces HO-1 expression and transformation throughthe G 12/13 family of heterotrimeric G proteins and the smallGTPase RhoA. Targeted small hairpinRNAknockdown expressionof G 12, G 13, or RhoA and inhibition of RhoA activityimpair vGPCR-induced transformation and ho-1 promoteractivity. Knockdown expression of RhoA also reduces vGPCRinducedVEFG-A secretion and blocks tumor growth in amurine allograft tumor model. NIH-3T3 cells expressing constitutivelyactivatedG 13 orRhoAimplanted in nude mice developtumors displaying spindle-shaped cells that express HO-1 andVEGF-A, similarly to vGPCR-derived tumors. RhoAQL-inducedtumor growth is reduced 80% by small hairpin RNA-mediatedknockdown expression of HO-1 in the implanted cells.Likewise, inhibition of HO-1 activity by chronic administrationof the HO-1 inhibitor tin protoporphyrin IX to mice reducesRhoAQL-induced tumor growth by 70%. Our study shows thatvGPCR induces HO-1 expression through the G 12/13/RhoAaxes and shows for the first time a potential role for HO-1 as atherapeutic target in tumors whereRhoAhas oncogenic activity.