Role of H4 receptor in histamine-mediated responses in human melanoma

Abstract

We have previously reported that histamine at micromolar concentrations reduces the proliferation of melanoma cell lines. It is also known that melanoma cells express histamine H 1 , H 2 , and H 3 receptors. The aim of this study was to investigate the presence of histamine H 4 receptor (H 4 R) in human melanoma cells and its associated biological processes. To better understand the importance of histamine in tumor development, we explored the expression of H 4 R in human melanoma tissue biopsies. The expression of H 4 R in WM35 and M1/15 cells was analyzed by reverse-transcription-PCR, western blot, and immunocytochemistry. To characterize the biological responses we evaluated cell proliferation by clonogenic assay and 5-bromo-2 0 -deoxyuridine incorporation. In addition, cell senescence and differentiation were determined by b-galactosidase enzyme assay and dopa oxidase activity, respectively. The expression levels of H 4 R were determined by immunohistochemistry in 19 samples of human malignant lesions. Results indicate that melanoma cells express H 4 R at the messenger RNA and protein levels. By using histamine agonists, antagonists, and H 4 R small-interfering RNA we showed that the inhibitory effect of histamine on proliferation was in part mediated through the stimulation of the H 4 R. The decrease in proliferation was associated with an induction of cell senescence and an increase in melanogenesis, which is a differentiation marker of these cells. Furthermore, H 4 R was expressed in 42% of human melanoma biopsies. To our knowledge, this is the first report that describes the presence of the H 4 R in melanoma cells and tissue, suggesting a potential therapeutic application of H 4 R ligands.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…The H 4 receptor has been shown to mediate cell cycle arrest in hematopoietic progenitor cells induced by growth factors (Petit-Bertron et al, 2009). In addition, activation of the receptor appears to inhibit proliferation of several human cancer cell lines (Massari et al, 2011(Massari et al, , 2013. The release of adrenocorticotropic hormone from a mouse pituitary tumor cell line via H 4 receptor activation has also been reported (Meng et al, 2008).…”

Histamine therapeutic efficacy in metastatic melanoma: Role of histamine H4 receptor agonists and opportunity for combination with radiation

“…Although there are several studies describing the action of histamine as a modulator of proliferation of certain tumors, its role in malignant melanoma is still inconclusive [5, 8, 9, 10]. It seems that histamine effect on tumor proliferation depends on the cell type, the balance between different receptor subtypes expressed, the concentration of histamine reached in the tumoral environment and the effectors activated, among others.…”

“…On the other side, it was demonstrated by using histamine agonists, antagonists and genetic tools, that histamine treatment produced an inhibitory effect on proliferation mediated in part through the stimulation of the H 4 R in WM35 and M1/15 human melanoma cells. In vivo experiments on M1/15 human primary melanoma experimental model demonstrated that mice receiving histamine or clozapine (H 4 R agonist) showed an increased median survival associated to a decrease in tumor growth and intratumoral neovascularization [8, 9]. In line with these results, numerous phase II and III clinical trials in metastatic melanoma demonstrated clinical benefits of histamine (Ceplene, a synthetic derivative of histamine) as an adjuvant to immunotherapy with IL-2, especially in melanoma patients with liver metastases [14].…”

“…Histamine dihydrochloride inhibits the formation of reactive oxygen species from monocytes/macrophages by suppressing the activity of NADPH oxidase, and thus preventing the inactivation of T cells and NK cells [15]. In addition, it is not possible to discard a direct action of histamine on melanoma cells, considering that the expression of H 1 R, H 2 R, H 3 R and H 4 R in human melanoma cell lines was shown [8, 12, 16]. In addition, literature suggests that those with allergy have a reduced risk of developing cancer versus the general population [17] and that a history of asthma may be a protective factor in cutaneous melanoma [18].…”

Identification of histamine receptors in the canine gastrointestinal tract

“…69 Also, the influence of H4 receptor-mediated inhibition of proliferation has been demonstrated in melanoma and breast cancer cells. 70 …”