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 and tumorigenesis

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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 contri...

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Detalles Bibliográficos
Autores principales:	Martín, M.J., Tanos, T., García, A.B., Martin, D., Gutkind, J.S., Coso, O.A., Marinissen, M.J.
Formato:	JOUR
Materias:	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 photosensitizing agent 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 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
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00219258_v282_n47_p34510_Martin
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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Sumario:	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.

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 and tumorigenesis

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