The Role of Cyclooxygenase-2 in Mediating the Effects of Histamine on Cell Proliferation and Vascular Endothelial Growth Factor Production in Colorectal Cancer

Abstract

Purpose: Activity of histidine decarboxylase, the key enzyme in the synthesis of histamine, has been shown to be increased in several types of human tumors.We attempted to establish whether the possible involvement of histidine decarboxylase and histamine in colorectal carcinogenesis might be mediated by the activation of the cyclooxygenase-2 (COX-2) pathway. Experimental Design: Expression/activity of histidine decarboxylase, histamine content, and prostaglandin E 2 (PGE 2 ) production were analyzed in 33 colorectal cancer samples and in the HT29, Caco-2, and HCT116 colon cancer cell lines. The effects of histamine, celecoxib, and H 1 , H 2 , and H 4 receptor antagonists on COX-2 expression/activity, cell proliferation, and vascular endothelial growth factor (VEGF) production were assessed in the three colon cancer lines that showed different constitutive COX-2 expression. Results: We showed the up-regulation of histidine decarboxylase protein expression and activity in the tumor specimens when compared with normal colonic mucosa. Histidine decarboxylase activity and histamine content were also significantly higher in metastatic tumors than in nonmetastatic ones.These variables significantly correlated with tumor PGE 2 production.The administration of histamine increased COX-2 expression/activity, cell proliferation, and VEGF production in the COX-2-positive HT29 and Caco-2 cells. Treatment with either H 2 /H 4 receptor antagonists or celecoxib prevented these effects. Histamine had no effect on both the COX-2 pathway andVEGF production in the COX-2-negative HCT116 cells. Conclusions: Our data showed that histamine exerts both a proproliferative and a proangiogenic effect via H 2 /H 4 receptor activation. These effects are likely to be mediated by increasing COX-2-related PGE 2 production in COX-2-expressing colon cancer cells.

The role of histamine in human mammary carcinogenesis: H3 and H4 receptors as potential therapeutic targets for breast cancer treatment.

“…2A). The specificity of these two antibodies was previously established by other methodologies elsewhere 37 and we confirmed it by the positive staining of infiltrating mast cells within breast specimen (data not shown).…”

Activation of the Central Histaminergic System is Involved in Hypoxia-Induced Stroke Tolerance in Adult Mice

“…Neuroprotection induced by hypoxic exposure is diminished by administration of the anti-VEGFR2/Flk1 blocking antibody or by the use of mutant mice lacking the hormone response element of the VEGF gene promoter in newborn mice (Laudenbach et al, 2007). Histamine enhances VEGF production in the granulation tissue and in cyclooxygenase-2-positive HT29 and Caco-2 cells through the H 2 receptor (Cianchi et al, 2005;Ghosh et al, 2001Ghosh et al, , 2002. We also found that endogenous histamine induced the expression of VEGF mRNA and protein in the cerebral cortex on exposure to hypoxia.…”

Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis

“…Then, we quantified and analysed the kinetics of calcium accumulation in the mitochondrial compartment of HeLa and HCT116 cells in microtiter plates (Materials and methods). After stimulation of cells with A23 or an IP 3 -mobilizing agent (histamine (Hist) that only acts on HeLa, but not on HCT116 cells (Cianchi et al, 2005)), Ca 2 þ m increased rapidly within seconds. In contrast, treatment with an inhibitor of N-glycosylation (tunicamycin (TN)) (McDowell and Schwarz, 1988) or an inhibitor of SERCA pumps (thapsigargin (TG)) (Inesi and Sagara, 1992) (Figures 1c and d).…”