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.

Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome

“…Because AGMO itself is down-regulated by the proinflammatory stimulus IFN-γ/LPS, this may be part of a complex regulatory network. Alterations of the plasma profile observed in tumor-bearing mice upon pharmacological inhibition of tetrahydrobiopterin biosynthesis (24) are compatible with such a proinflammatory mechanism of AGMO/tetrahydrobiopterin. On the other hand, submicromolar amounts of alkylglycerols, the substrates of AGMO, have been reported to act on lymphocytes by increasing IFN-γ and decreasing IL-4 formation (25), thus acting in a proinflammatory way, and their degradation by AGMO would be antiinflammatory.…”

The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression

“…Proteasomal degradation of GCH1 is blocked by metformin-induced AMPK activation resulting in the recoupling of eNOS in endothelial cells (40, 41). On the other hand there is a recent report indicating that in some tumors GCH1 expression might actually be increased (42). This study did not, however, evaluate functional consequence such as BH4:BH2 or cGMP.…”

Lipoprotein(a) and its role in inflammation, atherosclerosis and malignancies

“…It has been demonstrated that Lp(a) promotes the differentiation of pro-inflammatory, M1-type macrophages, that secrete a set of pro-inflammatory cytokines (e. g. interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α) and chemokines, like ‘interferon-gamma-induced protein-10’ (IP10, CXCL10) and ‘Regulated on Activation, Normal T‑cell Expressed and Secreted’ (RANTES, CCL5), leading to activation of T‑helper-1 (Th1) cells and natural killer (NK) cells [22–25]. The chemokines CXCL10 and RANTES are accompanied with inhibition of angiogenesis, which may affect function of vasa vasorum [25].…”