The Gα12/13 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...

• Autores: Martín, M.J.; Tanos, T.; García, A.B.; Martin, D.; Gutkind, J.S.; Coso, O.A.; Marinissen, M.J.
• Año de publicación: 2007
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: J. Biol. Chem. 2007;282(47):34510-34524
• Materia: Kaposi sarcoma lesions; Oncogenic activity; Tumor growth; Tumorigenesis; Cells; Enzyme activity; Gene expression; RNA; Tumors; Proteins; G protein coupled receptor; guanine nucleotide binding protein; guanine nucleotide binding protein alpha12; guanine nucleotide binding protein alpha13; guanosine triphosphatase; heme oxygenase 1; heme oxygenase inhibitor; heterotrimeric guanine nucleotide binding protein; protoporphyrin; RhoA guanine nucleotide binding protein; short hairpin RNA; unclassified drug; vasculotropin A; chemokine receptor; G protein coupled receptor, Human herpesvirus 8; G protein-coupled receptor, Human herpesvirus 8; guanine nucleotide binding protein alpha subunit; heme oxygenase 1; photosensitizing agent; protoporphyrin; RhoA guanine nucleotide binding protein; RHOA protein, human; VEGFA protein, human; allograft; animal cell; animal experiment; animal model; article; carcinogenesis; cell proliferation; cell strain 3T3; cell survival; controlled study; enzyme activity; human; human cell; Human herpesvirus 8; Kaposi sarcoma; mouse; nonhuman; nude mouse; priority journal; protein expression; protein function; tumor growth; animal; drug antagonism; drug effect; drug screening; gene expression regulation; genetics; Human herpesvirus 8; metabolism; promoter region; secretion; virus cell transformation; Herpesviridae; Murinae; Mus; Mus musculus; Animals; Cell Transformation, Viral; Gene Expression Regulation, Neoplastic; GTP-Binding Protein alpha Subunits, Gq-G11; Heme Oxygenase-1; Herpesvirus 8, Human; Humans; Mice; Mice, Nude; NIH 3T3 Cells; Photosensitizing Agents; Promoter Regions (Genetics); Protoporphyrins; Receptors, Chemokine; rhoA GTP-Binding Protein; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays
• Institución: Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales

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 Gα12/13 family of heterotrimeric G proteins and the small GTPase RhoA. Targeted small hairpin RNA knockdown expression of Gα12, Gα13, 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 Gα13 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 Gα12/13/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.
Fil:Tanos, T. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Coso, O.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.