title: Inhibition of GTP cyclohydrolase attenuates tumor growth by reducing angiogenesis and M2-like polarization of tumor associated macrophages.
abstract: GTP cyclohydrolase (GCH1) is the key-enzyme to produce the essential enzyme cofactor, tetrahydrobiopterin. The byproduct, neopterin is increased in advanced human cancer and used as cancer-biomarker, suggesting that pathologically increased GCH1 activity may promote tumor growth. We found that inhibition or silencing of GCH1 reduced tumor cell proliferation and survival and the tube formation of human umbilical vein endothelial cells, which upon hypoxia increased GCH1 and endothelial NOS expression, the latter prevented by inhibition of GCH1. In nude mice xenografted with HT29-Luc colon cancer cells GCH1 inhibition reduced tumor growth and angiogenesis, determined by in vivo luciferase and near-infrared imaging of newly formed blood vessels. The treatment with the GCH1 inhibitor shifted the phenotype of tumor associated macrophages from the proangiogenic M2 towards M1, accompanied with a shift of plasma chemokine profiles towards tumor-attacking chemokines including CXCL10 and RANTES. GCH1 expression was increased in mouse AOM/DSS-induced colon tumors and in high grade human colon and skin cancer and oppositely, the growth of GCH1-deficient HT29-Luc tumor cells in mice was strongly reduced. The data suggest that GCH1 inhibition reduces tumor growth by (i) direct killing of tumor cells, (ii) by inhibiting angiogenesis, and (iii) by enhancing the antitumoral immune response.
authors: Pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Goethe-Universität, Frankfurt, Germany.
authors: Geethanjali
authors: G
authors: Pickert
authors: Hee-Young
authors: HY
authors: Lim
authors: Andreas
authors: A
authors: Weigert
authors: Annett
authors: A
authors: Häussler
authors: Thekla
authors: T
authors: Myrczek
authors: Maximilian
authors: M
authors: Waldner
authors: Sandra
authors: S
authors: Labocha
authors: Nerea
authors: N
authors: Ferreirós
authors: Gerd
authors: G
authors: Geisslinger
authors: Jörn
authors: J
authors: Lötsch
authors: Christoph
authors: C
authors: Becker
authors: Bernhard
authors: B
authors: Brüne
authors: Irmgard
authors: I
authors: Tegeder
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018925:Chemokines / Q000097:blood; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D019798:Neopterin / Q000096:biosynthesis; D009389:Neovascularization, Pathologic; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D012878:Skin Neoplasms / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; D018925:Chemokines; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D001708:Biopterins; D019798:Neopterin; D052250:Nitric Oxide Synthase Type III; D006136:GTP Cyclohydrolase; C003402:sapropterin