Exp Mol Med.  2007 Jun;39(3):284-294.

Histamine and spontaneously released mast cell granules ffect the cell growth of human hepatocellular carcinoma cells

• Lampiasi N
• Azzolina A
• Montalto G
• Cervello M

Abstract

The role of mast cells in tumor growth is still controversial. In this study we analyzed the effects of both histamine and pre-formed mediators spontaneously released by mast cells on the growth of two human hepatocellular carcinoma cell lines, HA22T/VGH and HuH-6, with different characteristics of differentiation, biological behavior and genetic defects. We showed that total mast cell releasate, exocytosed granules (granule remnants) and histamine reduced cell viability and proliferation in HuH-6 cells. In contrast, in HA22T/VGH cells granule remnants and histamine induced a weak but significant increase in cell growth. We showed that both cell lines expressed histamine receptors H1 and H2 and that the selective H1 antagonist terfenadine reverted the histamine-induced inhibition of HuH-6 cell growth, whereas the selective H2 antagonist ranitidine inhibited the histamine-induced cell growth of HA22T/VGH cells. We demonstrated that histamine down-regulated the expression of beta-catenin, COX-2 and survivin in HuH-6 cells and that this was associated with caspase-3 activation and PARP cleavage. On the contrary, in HA22T/VGH cells expression of survivin and beta-catenin increased after treatment with granule remnants and histamine. Overall, our results suggest that mediators stored in mast cell granules and histamine may affect the growth of liver cancer cells. However, mast cells and histamine may play different roles depending on the tumor cell features. Finally, these data suggest that histamine and histamine receptor agonists/antagonists might be considered as "new therapeutic" drugs to inhibit liver tumor growth.

Keyword

beta-catenin; BIRC5 protein, human; carcinoma, hepatocellular; cyclooxygenase 2; histamine; mast cells

MeSH Terms

Animals
Apoptosis
Carcinoma, Hepatocellular/*metabolism/*pathology
Caspase 3/metabolism
Cell Line, Tumor
Cell Proliferation
Cell Survival
Cells, Cultured
Cyclooxygenase 2/metabolism
Enzyme Activation
Exocytosis
Female
Histamine/*pharmacology
Histamine Antagonists/pharmacology
Humans
Liver Neoplasms/*metabolism/*pathology
Mast Cells/*physiology
Microtubule-Associated Proteins/metabolism
Neoplasm Proteins/metabolism
Poly(ADP-ribose) Polymerases/metabolism
Ranitidine/pharmacology
Rats
Rats, Wistar
Receptors, Histamine/metabolism
Terfenadine/pharmacology
beta Catenin/metabolism