Inhibition of heme oxygenase-1 interferes with the transforming activity of the Kaposi sarcoma herpesvirus-encoded G protein-coupled receptor.
Heme oxygenase-1 (HO-1), the inducible enzyme responsible for the rate-limiting step in the heme catabolism, is expressed in AIDS-Kaposi sarcoma (KS) lesions. Its expression is up-regulated by the Kaposi sarcoma-associated herpesvirus (KSHV) in endothelial cells, but the mechanisms underlying KSHV-induced HO-1 expression are still unknown. In this study we investigated whether the oncogenic G protein-coupled receptor (KSHV-GPCR or vGPCR), one of the key KSHV genes involved in KS development, activated HO-1 expression. Here we show that vGPCR induces HO-1 mRNA and protein levels in fibroblasts and endothelial cells. Moreover, targeted knock-down gene expression of HO-1 by small hairpin RNA and chemical inhibition of HO-1 enzymatic activity by tin protoporphyrin IX (SnPP), impaired vGPCR-induced survival, proliferation, transformation, and vascular endothelial growth factor (VEGF)-A expression. vGPCR-expressing cells implanted in the dorsal flank of nude mice developed tumors with elevated HO-1 expression and activity. Chronic administration of SnPP to the implanted mice, under conditions that effectively blocked HO-1 activity and VEGF-A expression in the transplanted cells, strikingly reduced tumor growth, without apparent side effects. On the contrary, administration of the HO-1 inducer cobalt protoporphyrin (CoPP) further enhanced vGPCR-induced tumor growth. These data postulate HO-1 as an important mediator of vGPCR-induced tumor growth and suggest that inhibition of intratumoral HO-1 activity by SnPP may be a potential therapeutic strategy.
Marinissen
Maria Julia
MJ
Instituto de Investigaciones Biomédicas A. Sols Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid 28029, Spain. mjmarinissen@iib.uam.es
Tanos
Tamara
T
Bolós
Marta
M
de Sagarra
Maria Rosa
MR
Coso
Omar A
OA
Cuadrado
Antonio
A
D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002470:Cell Survival; D016895:Culture Media, Serum-Free / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D017930:Genes, Reporter; D006418:Heme / Q000737:chemistry; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D008665:Metalloporphyrins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011524:Protoporphyrins / Q000737:chemistry / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D017304:Annexin A5; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D042461:Vascular Endothelial Growth Factor A; D006418:Heme; D012313:RNA; C007095:cobaltiprotoporphyrin; D004247:DNA; C032628:tin protoporphyrin IX; D008156:Luciferases; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1