The role of cyclooxygenase-2 in mediating the effects of histamine on cell proliferation and vascular endothelial growth factor production in colorectal cancer.
OBJECTIVE
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.


METHODS
Expression/activity of histidine decarboxylase, histamine content, and prostaglandin E2 (PGE2) 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 H1, H2, and H4 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 H2/H4 receptor antagonists or celecoxib prevented these effects. Histamine had no effect on both the COX-2 pathway and VEGF production in the COX-2-negative HCT116 cells.


CONCLUSIONS
Our data showed that histamine exerts both a proproliferative and a proangiogenic effect via H2/H4 receptor activation. These effects are likely to be mediated by increasing COX-2-related PGE2 production in COX-2-expressing colon cancer cells.
Cianchi
Fabio
F
Department of General Surgery, Medical School, University of Florence, Italy. cianchif@mail.unifi.it
Cortesini
Camillo
C
Schiavone
Nicola
N
Perna
Federico
F
Magnelli
Lucia
L
Fanti
Elena
E
Bani
Daniele
D
Messerini
Luca
L
Fabbroni
Valentina
V
Perigli
Giuliano
G
Capaccioli
Sergio
S
Masini
Emanuela
E
D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D018938:Caco-2 Cells; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006632:Histamine / Q000378:metabolism*; D006640:Histidine Decarboxylase / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000378:metabolism; D000074040:Receptors, Histamine H4; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; C418607:HRH4 protein, human; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D011970:Receptors, Histamine H2; D000074040:Receptors, Histamine H4; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D006632:Histamine; D051546:Cyclooxygenase 2; D006640:Histidine Decarboxylase; D000068579:Celecoxib; D015232:Dinoprostone