EFFECT OF UROKINASE GENE KNOCKOUT ON TISSUE LEVELS OF BIOGENIC AMINES IN MICE WITH MELANOMA

The research aim was to study the dynamics of biogenic amines in the brain, tumor and intact skin of urokinase (uPA) gene knockout mice on day 21 of the B16/F10 melanoma growth. Material and methods. The study included male and female uPA gene knockout (–uPA, n = 38) and wild type mice (+uPA, n = 61). Melanoma was transplanted subcutaneously. Levels of biogenic amines were studied by ELISA in tissues obtained on day 21 of carcinogenesis. Results and discussion. Intact (–uPA) mice showed an increased total content of biogenic amines: in the skin – due to noradrenaline increase by 4.8 times in males and by 4.9 times in females, histamine – by 3.6 times in males and by 1.6 times (p < 0.05) in females, serotonin – by 3.4 times in males and by 8.3 times in females; in the brain – due to noradrenaline increase by 3.5 times in males and by 3.2 times in females, dopamine by 2.1 times in males and by 2.9 times in females, while histamine content decreased. Melanoma development in (–uPA) mice was characterized by: lower levels of adrenaline with high NA concentrations and an increase in the serotonin metabolism in the brain; higher histamine concentrations in the tumor and higher serotonin levels in the skin; similar to (+uPA) mice levels of adrenaline (males) and noradrenaline in the tumor and higher levels of adrenaline in the tumor and histamine in the skin in (–uPA) females. Conclusions. The uPA gene knockout limits the development of stress at the central regulatory level due to lower levels of A together with increasing serotoninergic mediation in the brain, as well as modulates the immune antitumor response due to higher levels of histamine in the tumor and 5 serotonin in the skin, as a result of lower monoamine oxidase activity, in mice with B16/F10 melanoma.

Agarwala S.S., Glaspy J., O'Day S.J., Mitchell M., Gutheil J., Whitman E., Gonzalez R., Hersh E., Feun L., Belt R., Meyskens F., Hellstrand K., Wood D. Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma. J. Clin. Oncol. 2002; 20: 125–133.

Calvani M., Cavallini L., Tondo A., Spinelli V., Ricci L., Pasha A., Bruno G., Buonvicino D., Bigagli E., Vignoli M., Bianchini F., Sartiani L., Lodovici M., Semeraro R., Fontani F., De Logu F., Dal Monte M., Chiarugi P., Favre C., Filippi L. β3-Adrenoreceptors control mitochondrial dormancy in melanoma and embryonic stem cells. Oxid. Med. Cell. Longev. 2018; 2018: 816508. doi: 10.1155/2018/6816508

Calvani M., Pelon F., Comito G., Taddei M.L., Moretti S., Innocenti S., Chiarugi P. Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression. Oncotarget. 2015; 6 (7): 4615–4632. doi:10.18632/oncotarget.2652

De Giorgi V., Grazzini M., Benemei S. Propranolol for off-label treatment of patients with melanoma: results from a cohort study. JAMA Oncol. 2018; 4 (2): ID e172908. doi: 10.1001/jamaoncol.2017.2908

Frantsiyants E.M., Kaplieva I.V., Surikova E.I., Neskubina I.V., Bandovkina V.A., Trepitaki L.K., Lesovaya N.S., Cheryarina N.D., Pogorelova Yu.A., Nemashkalova L.A. Effect of urokinase gene-knockout on growth of melanoma in experiment. Sibirskiy nauchnyy medtsinskiy zhurnal = Siberian Scientific Medical Journal. 2019; 39 (4): 62-70. [In Russian]. doi: 10.15372/SSMJ20190408

Jozic I., Stojadinovic O., Kirsner R.S., Tomic-Canic M. Skin under the (spot)-light: cross-talk with the central hypothalamic-pituitary-adrenal (HPA) axis. J. Invest. Dermatol. 2015; 135 (6): 1469–1471. doi: 10.1038/jid.2015.56

Kotieva I.M., Kit O.I., Frantsiyants E.M., Bandovkina V.A., Kaplieva I.V., Trepitaki L.K., Cheryarina N.D., Pogorelova Yu.A. Effect of experimental chronic pain on levels of biogenic amines in skin of mice in dynamics of B16/F10 melanoma growth. Izvestiya vysshikh uchebnykh zavedeniy. Severo-Kavkazskiy region. Estestvennyye nauki = University news. North-Caucasian region. Natural sciences series. 2018; 198 (1): 130-139. [In Russian].

Lee H.J., Park M.K., Kim S.Y., Park Choo H.Y., Lee A.Y. Serotonin induces melanogenesis via serotonin receptor 2A. Br. J. Dermatol. 2011; 165: 1344–1348. doi: 10.1111/j.1365-2133.2011.10490.x

Massari N.A., Medina V.A., Cricco G.P., Martinel Lamas D.J., Sambuco L., Pagotto R., Ventura C., Ciraolo P.J., Pignataro O., Bergoc R.M., Rivera E.S. Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma. J. Dermatol. Sci. 2013; 72: 252–262. doi: 10.1016/j.jdermsci.2013.07.012

Massari N.A., Nicoud M.B., Sambuco L., Cricco G.P., Martinel Lamas D.J., Herrero Ducloux M.V., Medina V.A. Histamine therapeutic efficacy in metastatic melanoma: Role of histamine H4 receptor agonists and opportunity for combination with radiation. Oncotarget. 2017; 8 (16): 26471–26491. doi: 10.18632/oncotarget.15594

Pang S., Wu H., Wang Q., Cai M., Shi W., Shang J. Chronic stress suppresses the expression of cutaneous hypothalamic-pituitary-adrenocortical axis elements and melanogenesis. PloS One. 2014; 9 (5): e98283. doi: 10.1371/journal.pone.0098283

Paus R., Theoharides T.C., Arck P.C. Neuroimmunoendocrine circuitry of the 'brain-skin connection'. Trends Immunol. 2006; 27 (1): 32–39. doi: 10.1016/j.it.2005.10.002.

Pérez-Guijarro E., Day C.P., Merlino G., Zaidi M.R. Genetically engineered mouse models of melanoma. Cancer. 2017; 123 (S11): 2089–2103. doi: 10.1002/cncr.30684

Slominski A., Wortsman J. Neuroendocrinology of the skin. Endocr. Rev. 2000; 21: 457–487. doi: 10.1210/edrv.21.5.0410

Slominski A.T., Zmijewski M.A., Skobowiat C., Zbytek B., Slominski R.M., Steketee J.D. Sensing the environment: regulation of local and global homeostasis by the skin's neuroendocrine system. Adv. Anat. Embryol. Cell. Biol. 2012; 212 (v, vii): 1–115. doi: 10.1007/978-3-642-19683-6_1

Slominski A.T., Zmijewski M.A., Zbytek B., Tobin D.J., Theoharides T.C. Key role of CRF in the skin stress response system. Endocr. Rev. 2013; 34: 827–884. doi: 10.1210/er.2012-1092

Tchernev G., Lozev I., Temelkova I., Chernin S., Yungareva I. Schizophrenia as potential trigger for melanoma development and progression! The psycho-neuro-endocrine-oncology (P.N.E.O) network! Open Access Maced. J. Med. Sci. 2018; 6 (8): 1442-1445. doi: 10.3889/oamjms.2018.276

Wu H., Zhao Y.,  Huang Q., Cai M., Pan Q.,  Fu M.,  An X., Xia Z., Liu M., Jin Y.,  He L.,  Shang J. NK1R/5-HT1AR interaction is related to the regulation of melanogenesis. FASEB J. 2018; 32 (6): 3193-3214. doi: 10.1096/fj.201700564RR.

Wu H.L., Pang S.L., Liu Q.Z., Wang Q., Cai M.X., Shang, J. 5-HT1A/1B receptors as targets for optimizing pigmentary responses in C57BL/6 mouse skin to stress. PloS One. 2014; 9 (2): e89663. doi: 10.1371/journal.pone.0089663

Zhang X., Yu M., Yu W., Weinberg J., Shapiro J. Development of alopecia areata is associated with higher central and peripheral hypothalamic-pituitary-adrenal tone in the skin graft induced C3H/HeJ mouse model. J. Invest. Dermatol. 2009; 129: 1527–1538. doi: 10.1038/jid.2008.371

Neskubina I.V., e-mail: kaplirina@yandex.ru