title: 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.
abstract: Heme oxygenase-1 (HO-1), an inducible enzyme that metabolizes the heme group, is highly expressed in human Kaposi sarcoma lesions. Its expression is up-regulated by the G protein-coupled receptor from the Kaposi sarcoma-associated herpes virus (vGPCR). Although recent evidence shows that HO-1 contributes to vGPCR-induced tumorigenesis and vascular endothelial growth factor (VEGF) expression, the molecular steps that link vGPCR to HO-1 remain unknown. Here we show that vGPCR induces HO-1 expression and transformation through the Galpha(12/13) family of heterotrimeric G proteins and the small GTPase RhoA. Targeted small hairpin RNA knockdown expression of Galpha(12), Galpha(13), or RhoA and inhibition of RhoA activity impair vGPCR-induced transformation and ho-1 promoter activity. Knockdown expression of RhoA also reduces vGPCR-induced VEFG-A secretion and blocks tumor growth in a murine allograft tumor model. NIH-3T3 cells expressing constitutively activated Galpha(13) or RhoA implanted in nude mice develop tumors displaying spindle-shaped cells that express HO-1 and VEGF-A, similarly to vGPCR-derived tumors. RhoAQL-induced tumor growth is reduced 80% by small hairpin RNA-mediated knockdown expression of HO-1 in the implanted cells. Likewise, inhibition of HO-1 activity by chronic administration of the HO-1 inhibitor tin protoporphyrin IX to mice reduces RhoAQL-induced tumor growth by 70%. Our study shows that vGPCR induces HO-1 expression through the Galpha(12/13)/RhoA axes and shows for the first time a potential role for HO-1 as a therapeutic target in tumors where RhoA has oncogenic activity.
authors: Instituto de Investigaciones Biomédicas A. Sols, Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, Madrid, Spain.
authors: María José
authors: MJ
authors: Martín
authors: Tamara
authors: T
authors: Tanos
authors: Ana Belén
authors: AB
authors: García
authors: Daniel
authors: D
authors: Martin
authors: J Silvio
authors: JS
authors: Gutkind
authors: Omar A
authors: OA
authors: Coso
authors: Maria Julia
authors: MJ
authors: Marinissen
mesh_terms: D000818:Animals; D002472:Cell Transformation, Viral / Q000187:drug effects; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D017319:Photosensitizing Agents / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011524:Protoporphyrins / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C115448:G protein-coupled receptor, Human herpesvirus 8; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D019707:Receptors, Chemokine; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C066737:RHOA protein, human; C028025:protoporphyrin IX; D051547:Heme Oxygenase-1; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020742:rhoA GTP-Binding Protein