Serotonin signalling in cancer: Emerging mechanisms and therapeutic opportunities

Abstract

• Primary synthesis and metabolic routes of peripheral 5-hydroxytryptamine in the gastrointestinal tract.

• Advanced research has established a strong association between the serotonergic components and carcinogenic mechanisms.

• The interplay between serotonergic signalling and the immune system within the tumour microenvironment orchestrates antitumour immune responses.

• Serotonergic-targeted drugs offer valuable clinical options for cancer therapy

Keywords

immunomodulatory function / serotonergic drugs / serotonin / serotonylation / tumourigenesis

References

[1] Whitaker-AzmitiaPM. The discovery of serotonin and its role in neuroscience. Neuropsychopharmacology. 1999;21:2S-8S.

[2] RapportMM, GreenAA, PageIH. Crystalline serotonin. Science. 1948;108:329-330.

[3] RapportMM, GreenAA, PageIH. Partial purification of the vasoconstrictor in beef serum. J Biol Chem. 1948;174:735-741.

[4] RapportMM, GreenAA, PageIH. Serum vasoconstrictor, serotonin; isolation and characterization. J Biol Chem. 1948;176:1243-1251.

[5] ErspamerV, AseroB. Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature. 1952;169:800-801.

[6] BrodieBB, ShorePA. A concept for a role of serotonin and norepinephrine as chemical mediators in the brain. Ann N Y Acad Sci. 1957;66:631-642.

[7] MichaelsonIA, Whittaker VP. The subcellular localization of 5-hydroxytryptamine in guinea pig brain. Biochem Pharmacol. 1963;12:203-211.

[8] ZieherLM, De Robertis E. Subcellular localization of 5-hydroxytryptamine in rat brain. Biochem Pharmacol. 1963;12:596-598.

[9] Veenstra-VanderWeeleJ, Anderson GM, CookEH. Pharmacogenetics and the serotonin system: initial studies and future directions. Eur J Pharmacol. 2000;410:165-181.

[10] ZamaniA, QuZ. Serotonin activates angiogenic phosphorylation signaling in human endothelial cells. FEBS Lett. 2012;586:2360-2365.

[11] YadavVK, BalajiS, SureshPS, et al. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat Med. 2010;16:308-312.

[12] MartinAM, YoungRL, LeongL, et al. The diverse metabolic roles of peripheral serotonin. Endocrinology. 2017;158:1049-1063.

[13] WaltherDJ, BaderM. A unique central tryptophan hydroxylase isoform. Biochem Pharmacol. 2003;66:1673-1680.

[14] YuPL, Fujimura M, OkumiyaK, KinoshitaM, Hasegawa H, FujimiyaM. Immunohistochemical localization of tryptophan hydroxylase in the human and rat gastrointestinal tracts. J Comp Neurol. 1999;411:654-665.

[15] GershonMD, Drakontides AB, RossLL. Serotonin: synthesis and release from the myenteric plexus of the mouse intestine. Science. 1965;149:197-199.

[16] GershonMD, TackJ. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132:397-414.

[17] YanoJM, YuK, DonaldsonGP, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161:264-276.

[18] ReigstadCS, Salmonson CE, RaineyJF, et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. 2015;29:1395-1403.

[19] ZhuP, LuT, ChenZ, et al. 5-Hydroxytryptamine produced by enteric serotonergic neurons initiates colorectal cancer stem cell self-renewal and tumorigenesis. Neuron. 2022;110:2268-2282. e2264.

[20] WaltherDJ, PeterJU, BashammakhS, et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science. 2003;299:76.

[21] MercadoCP, KilicF. Molecular mechanisms of SERT in platelets: regulation of plasma serotonin levels. Mol Interv. 2010;10:231-241.

[22] RiederM, Gauchel N, BodeC, DuerschmiedD. Serotonin: a platelet hormone modulating cardiovascular disease. J Thromb Thrombol. 2021;52:42-47.

[23] WaltherDJ, PeterJU, WinterS, et al. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Cell. 2003;115:851-862.

[24] BergerM, GrayJA, RothBL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355-366.

[25] ShajibMS, KhanWI. The role of serotonin and its receptors in activation of immune responses and inflammation. Acta Physiol (Oxf). 2015;213:561-574.

[26] McIsaacIW, PageIH. The metabolism of serotonin (5-hydroxytryptamine). J Biol Chem. 1959;234:858-864.

[27] TyceGM. Origin and metabolism of serotonin. J Cardiovasc Pharmacol. 1990;16(suppl 3):S1-S7.

[28] IchiyamaA, Nakamura S, NishizukaY, HayaishiO. Enzymic studies on the biosynthesis of serotonin in mammalian brain. J Biol Chem. 1970;245:1699-1709.

[29] HoyerD, ClarkeDE, FozardJR, et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev. 1994;46:157-203.

[30] DerkachV, Surprenant A., NorthRA. 5-HT3 receptors are membrane ion channels. Nature. 1989;339:706-709.

[31] Mohammad-ZadehLF, Moses L, Gwaltney-BrantSM. Serotonin: a review. J Vet Pharmacol Ther. 2008;31:187-199.

[32] KarmakarS, LalG. Role of serotonin receptor signaling in cancer cells and anti-tumor immunity. Theranostics. 2021;11:5296-5312.

[33] CerritoF, Raiteri M. Serotonin release is modulated by presynaptic autoreceptors. Eur J Pharmacol. 1979;57:427-430.

[34] YangD, GouauxE. Illumination of serotonin transporter mechanism and role of the allosteric site. Sci Adv. 2021;7:eabl3857.

[35] BaderM. Serotonylation: serotonin signaling and epigenetics. Front Mol Neurosci. 2019;12:288.

[36] DaleGL, FrieseP, BatarP, et al. Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface. Nature. 2002;415:175-179.

[37] BockaertJ, Becamel C, Chaumont-DubelS, ClaeysenS, Vandermoere F, MarinP. Novel and atypical pathways for serotonin signaling. Fac Rev. 2021;10:52.

[38] WattsSW, Priestley JR, ThompsonJM. Serotonylation of vascular proteins important to contraction. PLoS One. 2009;4:e5682.

[39] PaulmannN, Grohmann M, VoigtJP, et al. Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation. PLoS Biol. 2009;7:e1000229.

[40] MiZ, SiT, KapadiaK, Li Q, MumaNA. Receptor-stimulated transamidation induces activation of Rac1 and Cdc42 and the regulation of dendritic spines. Neuropharmacology. 2017;117:93-105.

[41] Ayme-DietrichE, LawsonR, Da-SilvaS, Mazzucotelli JP, MonassierL. Serotonin contribution to cardiac valve degeneration: new insights for novel therapies? Pharmacol Res. 2019;140:33-42.

[42] FarrellyLA, Thompson RE, ZhaoS, et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature. 2019;567:535-539.

[43] ZhaoS, ChuhKN, ZhangB, et al. Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout. Proc Natl Acad Sci U S A. 2021;118:e2016742118.

[44] SollC, RienerMO, OberkoflerCE, et al. Expression of serotonin receptors in human hepatocellular cancer. Clin Cancer Res. 2012;18:5902-5910.

[45] AbediniF, AmjadiO, Hedayatizadeh-OmranA, LiraSA, Ahangari G. Serotonin receptors and acetylcholinesterase gene expression alternations: the potential value on tumor microenvironment of gastric cancer. Oncology. 2023;101:415-424.

[46] PaiVP, Marshall AM, HernandezLL, BuckleyAR, Horseman ND. Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival. Breast Cancer Res. 2009;11:R81.

[47] SonierB, Arseneault M, LavigneC, OuelletteRJ, Vaillancourt C. The 5-HT2A serotoninergic receptor is expressed in the MCF-7 human breast cancer cell line and reveals a mitogenic effect of serotonin. Biochem Biophys Res Commun. 2006;343:1053-1059.

[48] LeeHJ, ParkMK, KimSY, Park Choo HY, LeeAY, LeeCH. Serotonin induces melanogenesis via serotonin receptor 2A. Br J Dermatol. 2011;165:1344-1348.

[49] BenhassineM, Le-BelG, GuerinSL. Contribution of the STAT family of transcription factors to the expression of the serotonin 2B (HTR2B) receptor in human uveal melanoma. Int J Mol Sci. 2022;23:1564.

[50] JiangSH, LiJ, DongFY, et al. Increased serotonin signaling contributes to the Warburg effect in pancreatic tumor cells under metabolic stress and promotes growth of pancreatic tumors in mice. Gastroenterology. 2017;153:277-291. e219.

[51] DizeyiN, Bjartell A, NilssonE, et al. Expression of serotonin receptors and role of serotonin in human prostate cancer tissue and cell lines. Prostate. 2004;59:328-336.

[52] DizeyiN, Bjartell A, HedlundP, TaskenKA, Gadaleanu V, AbrahamssonPA. Expression of serotonin receptors 2B and 4 in human prostate cancer tissue and effects of their antagonists on prostate cancer cell lines. Eur Urol. 2005;47:895-900.

[53] DizeyiN, Hedlund P, BjartellA, TinzlM, Austild-Tasken K, AbrahamssonPA. Serotonin activates MAP kinase and PI3K/Akt signaling pathways in prostate cancer cell lines. Urol Oncol. 2011;29:436-445.

[54] LiuY, ZhangH, WangZ, Wu P, GongW. 5-Hydroxytryptamine1a receptors on tumour cells induce immune evasion in lung adenocarcinoma patients with depression via autophagy/pSTAT3. Eur J Cancer. 2019;114:8-24.

[55] HenriksenR, DizeyiN, AbrahamssonPA. Expression of serotonin receptors 5-HT1A, 5-HT1B, 5-HT2B and 5-HT4 in ovary and in ovarian tumours. Anticancer Res. 2012;32:1361-1366.

[56] SiddiquiEJ, Shabbir MA, MikhailidisDP, MumtazFH, Thompson CS. The effect of serotonin and serotonin antagonists on bladder cancer cell proliferation. BJU Int. 2006;97:634-639.

[57] AlpiniG, Invernizzi P, GaudioE, et al. Serotonin metabolism is dysregulated in cholangiocarcinoma, which has implications for tumor growth. Cancer Res. 2008;68:9184-9193.

[58] TuttonPJ, BarklaDH. The influence of serotonin on the mitotic rate in the colonic crypt epithelium and in colonic adenocarcinoma in rats. Clin Exp Pharmacol Physiol. 1978;5:91-94.

[59] TuttonPJ, BarklaDH. Neural control of colonic cell proliferation. Cancer. 1980;45:1172-1177.

[60] AtaeeR, AjdaryS, ZarrindastM, Rezayat M, HayatbakhshMR. Anti-mitogenic and apoptotic effects of 5-HT1B receptor antagonist on HT29 colorectal cancer cell line. J Cancer Res Clin Oncol. 2010;136:1461-1469.

[61] AtaeeR, AjdaryS, RezayatM, Shokrgozar MA, ShahriariS, ZarrindastMR. Study of 5HT3 and HT4 receptor expression in HT29 cell line and human colon adenocarcinoma tissues. Arch Iran Med. 2010;13:120-125.

[62] AtaeeR, AjdaryS, ZarrindastM, Rezayat M, ShokrgozarMA, AtaeeA. Y25130 hydrochloride, a selective 5HT3 receptor antagonist has potent antimitogenic and apoptotic effect on HT29 colorectal cancer cell line. Eur J Cancer Prev. 2010;19:138-143.

[63] LiuH, HuangQ, FanY, LiB, LiuX, HuC. Dissecting the novel abilities of aripiprazole: the generation of anti-colorectal cancer effects by targeting Galphaq via HTR2B. Acta Pharm Sin B. 2023;13:3400-3413.

[64] SuiH, XuH, JiQ, et al. 5-Hydroxytryptamine receptor (5-HT1DR) promotes colorectal cancer metastasis by regulating Axin1/beta-catenin/MMP-7 signaling pathway. Oncotarget. 2015;6:25975-25987.

[65] LiuS, MiaoR, ZhaiM, et al. Effects and related mechanisms of serotonin on malignant biological behavior of hepatocellular carcinoma via regulation of Yap. Oncotarget. 2017;8:47412-47424.

[66] SollC, JangJH, RienerMO, et al. Serotonin promotes tumor growth in human hepatocellular cancer. Hepatology. 2010;51:1244-1254.

[67] YueY, ZhongM, AnX, et al. Serotonin (5-HT) 2A receptor involvement in melanin synthesis and transfer via activating the PKA/CREB signaling pathway. Int J Mol Sci. 2022;23:6111.

[68] KopparapuPK, TinzlM, AnagnostakiL, PerssonJL, DizeyiN. Expression and localization of serotonin receptors in human breast cancer. Anticancer Res. 2013;33:363-370.

[69] GautamJ, Banskota S, RegmiSC, et al. Tryptophan hydroxylase 1 and 5-HT(7) receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling. Mol Cancer. 2016;15:75.

[70] GwynneWD, Shakeel MS, Girgis-GabardoA, et al. Antagonists of the serotonin receptor 5A target human breast tumor initiating cells. BMC Cancer. 2020;20:724.

[71] Sola-PennaM, PaixaoLP, BrancoJR, et al. Serotonin activates glycolysis and mitochondria biogenesis in human breast cancer cells through activation of the Jak1/STAT3/ERK1/2 and adenylate cyclase/PKA, respectively. Br J Cancer. 2020;122:194-208.

[72] ChaudharyP, Guragain D, ChangJH, KimJA. TPH1 and 5-HT(7) receptor overexpression leading to gemcitabine-resistance requires non-canonical permissive action of EZH2 in pancreatic ductal adenocarcinoma. Cancers (Basel). 2021;13:5305.

[73] GurbuzN, AshourAA, AlpaySN, Ozpolat B. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells. PLoS One. 2014;9:e110067.

[74] WuW, LiQ, ZhuZ, et al. HTR1D functions as a key target of HOXA10-AS/miR-340-3p axis to promote the malignant outcome of pancreatic cancer via PI3K-AKT signaling pathway. Int J Biol Sci. 2022;18:3777-3794.

[75] LiangC, ChenW, ZhiX, et al. Serotonin promotes the proliferation of serum-deprived hepatocellular carcinoma cells via upregulation of FOXO3a. Mol Cancer. 2013;12:14.

[76] SiddiquiEJ, Shabbir M, MikhailidisDP, ThompsonCS, MumtazFH. The role of serotonin (5-hydroxytryptamine1A and 1B) receptors in prostate cancer cell proliferation. J Urol. 2006;176:1648-1653.

[77] CattaneoMG, FesceR, VicentiniLM. Mitogenic effect of serotonin in human small cell lung carcinoma cells via both 5-HT1A and 5-HT1D receptors. Eur J Pharmacol. 1995;291:209-211.

[78] VicentiniLM, Cattaneo MG, FesceR. Evidence for receptor subtype cross-talk in the mitogenic action of serotonin on human small-cell lung carcinoma cells. Eur J Pharmacol. 1996;318:497-504.

[79] TuY, YaoS, ChenQ, Li W, SongY, ZhangP. 5-Hydroxytryptamine activates a 5-HT/c-Myc/SLC6A4 signaling loop in non-small cell lung cancer. Biochim Biophys Acta Gen Subj. 2022;1866:130093.

[80] DuX, WangT, WangZ, et al. 5-HT(7) receptor contributes to proliferation, migration and invasion in NSCLC cells. Onco Targets Ther. 2020;13:2139-2151.

[81] ChenJR, HuangMS, LeeYC, Lin MH, YangYF. Potential clinical value of 5-hydroxytryptamine receptor 3C as a prognostic biomarker for lung cancer. J Oncol. 2021;2021:1901191.

[82] LiuQ, SunH, LiuY, et al. HTR1A inhibits the progression of triple-negative breast cancer via TGF-beta canonical and noncanonical pathways. Adv Sci (Weinh). 2022;9:e2105672.

[83] ZuoX, ChenZ, CaiJ, et al. 5-Hydroxytryptamine receptor 1D aggravates hepatocellular carcinoma progression through FoxO6 in AKT-dependent and independent manners. Hepatology. 2019;69:2031-2047.

[84] FatimaS, ShiX, LinZ, et al. 5-Hydroxytryptamine promotes hepatocellular carcinoma proliferation by influencing beta-catenin. Mol Oncol. 2016;10:195-212.

[85] CinarV, Hamurcu Z, GulerA, NurdinovN, Ozpolat B. Serotonin 5-HT7 receptor is a biomarker poor prognostic factor and induces proliferation of triple-negative breast cancer cells through FOXM1. Breast Cancer. 2022;29:1106-1120.

[86] TuRH, WuSZ, HuangZN, et al. Neurotransmitter receptor HTR2B regulates lipid metabolism to inhibit ferroptosis in gastric cancer. Cancer Res. 2023;83:3868-3885.

[87] YuH, QuT, YangJ, Dai Q. Serotonin acts through YAP to promote cell proliferation: mechanism and implication in colorectal cancer progression. Cell Commun Signal. 2023;21:75.

[88] SaponaraE, Visentin M, BaschieriF, et al. Serotonin uptake is required for Rac1 activation in Kras-induced acinar-to-ductal metaplasia in the pancreas. J Pathol. 2018;246:352-365.

[89] DaiY, DudekNL, PatelTB, Muma NA. Transglutaminase-catalyzed transamidation: a novel mechanism for Rac1 activation by 5-hydroxytryptamine2A receptor stimulation. J Pharmacol Exp Ther. 2008;326:153-162.

[90] YeD, XuH, XiaH, ZhangC, TangQ, Bi F. Targeting SERT promotes tryptophan metabolism: mechanisms and implications in colon cancer treatment. J Exp Clin Cancer Res. 2021;40:173.

[91] TaoX, ChenQ, LiN, et al. Serotonin-RhoA/ROCK axis promotes acinar-to-ductal metaplasia in caerulein-induced chronic pancreatitis. Biomed Pharmacother. 2020;125:109999.

[92] LiuD, LiangCH, HuangB, et al. Tryptophan metabolism acts as a new anti-ferroptotic pathway to mediate tumor growth. Adv Sci (Weinh). 2023;10:e2204006.

[93] QinL, ZhaoD, XuJ, et al. The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1. Blood. 2013;121:2154-2164.

[94] NocitoA, DahmF, JochumW, et al. Serotonin regulates macrophage-mediated angiogenesis in a mouse model of colon cancer allografts. Cancer Res. 2008;68:5152-5158.

[95] AsadaM, Ebihara S, YamandaS, et al. Depletion of serotonin and selective inhibition of 2B receptor suppressed tumor angiogenesis by inhibiting endothelial nitric oxide synthase and extracellular signal-regulated kinase 1/2 phosphorylation. Neoplasia. 2009;11:408-417.

[96] LeeJY, YangC, LimW, SongG. Methiothepin suppresses human ovarian cancer cell growth by repressing mitochondrion-mediated metabolism and inhibiting angiogenesis in vivo. Pharmaceutics. 2020;12:686.

[97] BanskotaS, GautamJ, RegmiSC, et al. BJ-1108, a 6-amino-2,4,5-trimethylpyridin-3-ol analog, inhibits serotonin-induced angiogenesis and tumor growth through PI3K/NOX pathway. PLoS One. 2016;11:e0148133.

[98] HerrN, BodeC, DuerschmiedD. The effects of serotonin in immune cells. Front Cardiovasc Med. 2017;4:48.

[99] de las Casas-EngelM, Dominguez-Soto A, Sierra-FilardiE, et al. Serotonin skews human macrophage polarization through HTR2B and HTR7. J Immunol. 2013;190:2301-2310.

[100] Dominguez-SotoA, Usategui A, Casas-EngelML, et al. Serotonin drives the acquisition of a profibrotic and anti-inflammatory gene profile through the 5-HT7R-PKA signaling axis. Sci Rep. 2017;7:14761.

[101] NietoC, RayoI, de Las Casas-EngelM, et al. Serotonin (5-HT) shapes the macrophage gene profile through the 5-HT(2B)-dependent activation of the aryl hydrocarbon receptor. J Immunol. 2020;204:2808-2817.

[102] DurkT, Panther E, MullerT, et al. 5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes. Int Immunol. 2005;17:599-606.

[103] SzaboA, Gogolak P, KonczG, et al. Immunomodulatory capacity of the serotonin receptor 5-HT2B in a subset of human dendritic cells. Sci Rep. 2018;8:1765.

[104] IdzkoM, Panther E, StratzC, et al. The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release. J Immunol. 2004;172:6011-6019.

[105] O'ConnellPJ, WangX, Leon-PonteM, Griffiths C, PingleSC, AhernGP. A novel form of immune signaling revealed by transmission of the inflammatory mediator serotonin between dendritic cells and T cells. Blood. 2006;107:1010-1017.

[106] ChenY, Leon-Ponte M, PingleSC, O'ConnellPJ, AhernGP. T lymphocytes possess the machinery for 5-HT synthesis, storage, degradation and release. Acta Physiol (Oxf). 2015;213:860-867.

[107] WanM, DingL, WangD, Han J, GaoP. Serotonin: a potent immune cell modulator in autoimmune diseases. Front Immunol. 2020;11:186.

[108] IkenK, ChhengS, FarginA, Goulet AC, KouassiE. Serotonin upregulates mitogen-stimulated B lymphocyte proliferation through 5-HT1A receptors. Cell Immunol. 1995;163:1-9.

[109] AbdouhM, Storring JM, RiadM, et al. Transcriptional mechanisms for induction of 5-HT1A receptor mRNA and protein in activated B and T lymphocytes. J Biol Chem. 2001;276:4382-4388.

[110] RinaldiA, Chiaravalli AM, MianM, et al. Serotonin receptor 3A expression in normal and neoplastic B cells. Pathobiology. 2010;77:129-135.

[111] SerafeimA, Grafton G, ChambaA, et al. 5-Hydroxytryptamine drives apoptosis in biopsylike Burkitt lymphoma cells: reversal by selective serotonin reuptake inhibitors. Blood. 2002;99:2545-2553.

[112] HernandezME, Martinez-Fong D, Perez-TapiaM, Estrada-GarciaI, Estrada-Parra S, PavonL. Evaluation of the effect of selective serotonin-reuptake inhibitors on lymphocyte subsets in patients with a major depressive disorder. Eur Neuropsychopharmacol. 2010;20:88-95.

[113] HellstrandK, Hermodsson S. Serotonergic 5-HT1A receptors regulate a cell contact-mediated interaction between natural killer cells and monocytes. Scand J Immunol. 1993;37:7-18.

[114] BettenA, Dahlgren C, HermodssonS, HellstrandK. Serotonin protects NK cells against oxidatively induced functional inhibition and apoptosis. J Leukoc Biol. 2001;70:65-72.

[115] EvansDL, LynchKG, BentonT, et al. Selective serotonin reuptake inhibitor and substance P antagonist enhancement of natural killer cell innate immunity in human immunodeficiency virus/acquired immunodeficiency syndrome. Biol Psychiatry. 2008;63:899-905.

[116] DuerschmiedD, SuidanGL, DemersM, et al. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood. 2013;121:1008-1015.

[117] SchneiderMA, HeebL, BeffingerMM, et al. Attenuation of peripheral serotonin inhibits tumor growth and enhances immune checkpoint blockade therapy in murine tumor models. Sci Transl Med. 2021;13:eabc8188.

[118] LiT, FuB, ZhangX, et al. Overproduction of gastrointestinal 5-HT promotes colitis-associated colorectal cancer progression via enhancing NLRP3 inflammasome activation. Cancer Immunol Res. 2021;9:1008-1023.

[119] ChanYL, LaiWC, ChenJS, et al. TIAM2S mediates serotonin homeostasis and provokes a pro-inflammatory immune microenvironment permissive for colorectal tumorigenesis. Cancers (Basel). 2020;12:1844.

[120] Di RossoME, SterleHA, CremaschiGA, Genaro AM. Beneficial effect of fluoxetine and sertraline on chronic stress-induced tumor growth and cell dissemination in a mouse model of lymphoma: crucial role of antitumor immunity. Front Immunol. 2018;9:1341.

[121] WangX, FuSQ, YuanX, et al. A GAPDH serotonylation system couples CD8(+) T cell glycolytic metabolism to antitumor immunity. Mol Cell. 2024;84:760-775. e767.

[122] WangX, LiB, KimYJ, et al. Targeting monoamine oxidase A for T cell-based cancer immunotherapy. Sci Immunol. 2021;6:eabh2383.

[123] WuJB, YinL, ShiC, et al. MAOA-dependent activation of Shh-IL6-RANKL signaling network promotes prostate cancer metastasis by engaging tumor-stromal cell interactions. Cancer Cell. 2017;31:368-382.

[124] LiJ, PuT, YinL, LiQ, LiaoCP, Wu BJ. MAOA-mediated reprogramming of stromal fibroblasts promotes prostate tumorigenesis and cancer stemness. Oncogene. 2020;39:3305-3321.

[125] TakaiD, YagiY, WakazonoK, et al. Silencing of HTR1B and reduced expression of EDN1 in human lung cancers, revealed by methylation-sensitive representational difference analysis. Oncogene. 2001;20:7505-7513.

[126] QinX, LiJ, WangS, et al. Serotonin/HTR1E signaling blocks chronic stress-promoted progression of ovarian cancer. Theranostics. 2021;11:6950-6965.

[127] SakitaJY, BaderM, SantosES, et al. Serotonin synthesis protects the mouse colonic crypt from DNA damage and colorectal tumorigenesis. J Pathol. 2019;249:102-113.

[128] MaoL, XinF, RenJ, et al. 5-HT2B-mediated serotonin activation in enterocytes suppresses colitis-associated cancer initiation and promotes cancer progression. Theranostics. 2022;12:3928-3945.

[129] YangH, XiaL, ChenJ, et al. Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity. Nat Med. 2019;25:1428-1441.

[130] LiuM, HuJ, MaT, WangS, DingH. Application of a disposable screen-printed electrode to depression diagnosis for laboratory rats based on blood serotonin detection. Anal Sci. 2011;27:839-843.

[131] ZongJC, WangX, ZhouX, et al. Gut-derived serotonin induced by depression promotes breast cancer bone metastasis through the RUNX2/PTHrP/RANKL pathway in mice. Oncol Rep. 2016;35:739-748.

[132] NishimuraJ, Hasegawa A, KudoT, et al. A phase II study of the safety of olanzapine for oxaliplatin based chemotherapy in colorectal patients. Sci Rep. 2021;11:4547.

[133] MarcinkuteM, Afshinjavid S, FatokunAA, JavidFA. Fluoxetine selectively induces p53-independent apoptosis in human colorectal cancer cells. Eur J Pharmacol. 2019;857:172441.

[134] GorR, GharibA, Dharshini BalajiP, MadhavanT, Ramalingam S. Inducing cytotoxicity in colon cancer cells and suppressing cancer stem cells by dolasetron and ketoprofen through inhibition of RNA binding protein PUM1. Toxics. 2023;11:669.

[135] LiM, DuanL, WuW, et al. Vortioxetine hydrobromide inhibits the growth of gastric cancer cells in vivo and in vitro by targeting JAK2 and SRC. Oncogenesis. 2023;12:24.

[136] ChenVC, HsuTC, LinCF, et al. Association of risperidone with gastric cancer: triangulation method from cell study, animal study, and cohort study. Front Pharmacol. 2022;13:846455.

[137] ZhangY, HuangQ, XuQ, JiaC, XiaY. Pimavanserin tartrate induces apoptosis and cytoprotective autophagy and synergizes with chemotherapy on triple negative breast cancer. Biomed Pharmacother. 2023;168:115665.

[138] RamachandranS, Kaushik IS, SrivastavaSK. Pimavanserin: a novel autophagy modulator for pancreatic cancer treatment. Cancers (Basel). 2021;13:5661.

[139] LiuZZ, LiuXN, FanRC, et al. Identification of pimavanserin tartrate as a potent Ca(2+)-calcineurin-NFAT pathway inhibitor for glioblastoma therapy. Acta Pharmacol Sin. 2021;42:1860-1874.

[140] LeeJY, LimW, SongG. Tumor-suppressive function of methiothepin in human placental choriocarcinoma cells. Reproduction. 2020;160:919-929.

[141] Del BelloF, Bonifazi A, GiorgioniG, et al. Chemical manipulations on the 1,4-dioxane ring of 5-HT(1A) receptor agonists lead to antagonists endowed with antitumor activity in prostate cancer cells. Eur J Med Chem. 2019;168:461-473.

[142] YangC, SongG, LimW. Methiothepin mesylate causes apoptosis of human prostate cancer cells by mediating oxidative stress and mitochondrial dysfunction. Free Radic Biol Med. 2020;150:12-22.

[143] DurandN, SimsirM, SignettiL, Labbal F, BallottiR, Mus-VeteauI. Methiothepin increases chemotherapy efficacy against resistant melanoma cells. Molecules. 2021;26:1867.

[144] AmbrosioMR, MagliE, CaliendoG, et al. Serotoninergic receptor ligands improve Tamoxifen effectiveness on breast cancer cells. BMC Cancer. 2022;22:171.

[145] LvGB, WangTT, ZhuHL, Wang HK, SunW, ZhaoLF. Vortioxetine induces apoptosis and autophagy of gastric cancer AGS cells via the PI3K/AKT pathway. FEBS Open Bio. 2020;10:2157-2165.

[146] HolstK, GusevaD, SchindlerS, et al. The serotonin receptor 5-HT(7)R regulates the morphology and migratory properties of dendritic cells. J Cell Sci. 2015;128:2866-2880.

[147] Leon-PonteM, AhernGP, O'ConnellPJ. Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor. Blood. 2007;109:3139-3146.

[148] RashidiM, BaziA, ShiranMR, et al. Tropisetron attenuates tumor growth and progression in an experimental model of mouse lung cancer. J Cell Biochem. 2020;121:1610-1622.

[149] LeeJS, ParkSY, KimNY, et al. Anti-tumor potential of a 5-HT3 receptor antagonist as a novel autophagy inducer in lung cancer: a retrospective clinical study with in vitro confirmation. J Clin Med. 2019;8:1380.

[150] LiuW, Stachura P, XuHC, et al. Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications. J Exp Clin Cancer Res. 2020;39:38.

[151] WangZ, ChenY, LiX, et al. Tegaserod maleate suppresses the growth of gastric cancer in vivo and in vitro by targeting MEK1/2. Cancers (Basel). 2022;14:3592.

[152] XuW, TamimH, ShapiroS, Stang MR, ColletJP. Use of antidepressants and risk of colorectal cancer: a nested case‒control study. Lancet Oncol. 2006;7:301-308.

[153] ZhangN, Sundquist J, SundquistK, JiJ. Use of selective serotonin reuptake inhibitors is associated with a lower risk of colorectal cancer among people with family history. Cancers (Basel). 2022;14:5905.

[154] BhagavathulaAS, WoolfB, RahmaniJ, Vidyasagar K, TesfayeW. Selective serotonin reuptake inhibitor use and the risk of hepatocellular carcinoma: a systematic review and dose-response analysis of cohort studies with one million participants. Eur J Clin Pharmacol. 2022;78:547-555.

[155] ChangCM, HsiehMS, YangTC, et al. Selective serotonin reuptake inhibitors and the risk of hepatocellular carcinoma in hepatitis B virus-infected patients. Cancer Manag Res. 2017;9:709-720.

[156] ChanHL, ChiuWC, ChenVC, et al. SSRIs associated with decreased risk of hepatocellular carcinoma: a population-based case‒control study. Psychooncology. 2018;27:187-192.

[157] BiJ, KhanA, TangJ, et al. Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug. Cell Rep. 2021;37:109957.

[158] MorchLS, Dehlendorff C, BaandrupL, FriisS, KjaerSK. Use of antidepressants and risk of epithelial ovarian cancer. Int J Cancer. 2017;141:2197-2203.

[159] LiuYC, ChenVC, LuML, et al. The association between selective serotonin reuptake inhibitors (SSRIs) use and the risk of bladder cancer: a nationwide population-based cohort study. Cancers (Basel). 2020;12:1184.

[160] van NoortV, Scholch S, IskarM, et al. Novel drug candidates for the treatment of metastatic colorectal cancer through global inverse gene-expression profiling. Cancer Res. 2014;74:5690-5699.

[161] LiuYX, WanS, YangXQ, et al. TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2. Cell Chem Biol. 2023;30:709-725. e706.

[162] Gil-AdI, Zolokov A, LomnitskiL, et al. Evaluation of the potential anti-cancer activity of the antidepressant sertraline in human colon cancer cell lines and in colorectal cancer-xenografted mice. Int J Oncol. 2008;33:277-286.

[163] DuarteD, Cardoso A, ValeN. Synergistic growth inhibition of HT-29 colon and MCF-7 breast cancer cells with simultaneous and sequential combinations of antineoplastics and CNS drugs. Int J Mol Sci. 2021;22:7408.

[164] DuarteD, RemaA, AmorimI, Vale N. Drug combinations: a new strategy to extend drug repurposing and epithelial‒mesenchymal transition in breast and colon cancer cells. Biomolecules. 2022;12:190.

[165] GeeraertsSL, KampenKR, RinaldiG, et al. Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis-addicted breast tumor growth. Mol Cancer Ther. 2021;20:50-63.

[166] AmsonR, PeceS, LespagnolA, et al. Reciprocal repression between P53 and TCTP. Nat Med. 2011;18:91-99.

[167] Boia-FerreiraM, Basilio AB, HamasakiAE, et al. TCTP as a therapeutic target in melanoma treatment. Br J Cancer. 2017;117:656-665.

[168] ShaoS, ZhuangX, ZhangL, Qiao T. Antidepressants fluoxetine mediates endoplasmic reticulum stress and autophagy of non-small cell lung cancer cells through the ATF4-AKT-mTOR signaling pathway. Front Pharmacol. 2022;13:904701.

[169] ChenS, XuanJ, WanL, et al. Sertraline, an antidepressant, induces apoptosis in hepatic cells through the mitogen-activated protein kinase pathway. Toxicol Sci. 2014;137:404-415.

[170] LinCJ, RobertF, SukariehR, Michnick S, PelletierJ. The antidepressant sertraline inhibits translation initiation by curtailing mammalian target of rapamycin signaling. Cancer Res. 2010;70:3199-3208.

[171] ZhangH, XuH, TangQ, Bi F. The selective serotonin reuptake inhibitors enhance the cytotoxicity of sorafenib in hepatocellular carcinoma cells. Anticancer Drugs. 2021;32:793-801.

[172] Leon-FerreRA, Majithia N, LoprinziCL. Management of hot flashes in women with breast cancer receiving ovarian function suppression. Cancer Treat Rev. 2017;52:82-90.

[173] ChoYW, KimEJ, NyiramanaMM, et al. Paroxetine induces apoptosis of human breast cancer MCF-7 cells through Ca(2+)- and p38 MAP kinase-dependent ROS generation. Cancers (Basel). 2019;11:64.

[174] GwynneWD, Hallett RM, Girgis-GabardoA, et al. Serotonergic system antagonists target breast tumor initiating cells and synergize with chemotherapy to shrink human breast tumor xenografts. Oncotarget. 2017;8:32101-32116.

[175] HallettRM, Girgis-Gabardo A, GwynneWD, et al. Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer. Oncotarget. 2016;7:53137-53152.

[176] ChinnapakaS, Bakthavachalam V, MunirathinamG. Repurposing antidepressant sertraline as a pharmacological drug to target prostate cancer stem cells: dual activation of apoptosis and autophagy signaling by deregulating redox balance. Am J Cancer Res. 2020;10:2043-2065.

[177] JiangX, LuW, ShenX, et al. Repurposing sertraline sensitizes non-small cell lung cancer cells to erlotinib by inducing autophagy. JCI Insight. 2018;3:e98921.

[178] ZinnahKMA, SeolJW, ParkSY. Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation. Int J Mol Med. 2020;46:795-805.

[179] DrinbergV, Bitcover R, RajchenbachW, PeerD. Modulating cancer multidrug resistance by sertraline in combination with a nanomedicine. Cancer Lett. 2014;354:290-298.

[180] PeerD, DekelY, MelikhovD, Margalit R. Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models. Cancer Res. 2004;64:7562-7569.

[181] ArgovM, KashiR, PeerD, Margalit R. Treatment of resistant human colon cancer xenografts by a fluoxetine-doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimen. Cancer Lett. 2009;274:118-125.

[182] GrassiL, NanniMG, RodinG, Li M, CarusoR. The use of antidepressants in oncology: a review and practical tips for oncologists. Ann Oncol. 2018;29:101-111.

[183] ZhengY, ChangX, HuangY, He D. The application of antidepressant drugs in cancer treatment. Biomed Pharmacother. 2023;157:113985.

[184] BoursiB, LurieI, HaynesK, Mamtani R, YangYX. Chronic therapy with selective serotonin reuptake inhibitors and survival in newly diagnosed cancer patients. Eur J Cancer Care (Engl). 2018;27.

[185] Matsushima-NishiwakiR, Kamoi S, KozawaO. Upregulation by duloxetine of the transforming growth factor-alpha-induced migration of hepatocellular carcinoma cells via enhancement of the c-Jun N-terminal kinase activity. Cell Biochem Funct. 2023;41:814-822.

[186] MorseMA, LiuE, JoishVN, et al. Antiproliferative effects of telotristat ethyl in patients with neuroendocrine tumors: the TELEACE real-world chart review study. Cancer Manag Res. 2020;12:6607-6614.

[187] MetzDC, LiuE, JoishVN, et al. Survival and clinical outcomes with telotristat ethyl in patients with carcinoid syndrome. Cancer Manag Res. 2020;12:9713-9719.

[188] PeehlDM, CoramM, KhineH, Reese S, NolleyR, ZhaoH. The significance of monoamine oxidase—a expression in high grade prostate cancer. J Urol. 2008;180:2206-2211.

[189] WuJB, ShaoC, LiX, et al. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. J Clin Invest. 2014;124:2891-2908.

[190] LiaoCP, LinTP, LiPC, et al. Loss of MAOA in epithelia inhibits adenocarcinoma development, cell proliferation and cancer stem cells in prostate. Oncogene. 2018;37:5175-5190.

[191] YinL, LiJ, WangJ, et al. MAOA promotes prostate cancer cell perineural invasion through SEMA3C/PlexinA2/NRP1-cMET signaling. Oncogene. 2021;40:1362-1374.

[192] WangYY, ZhouYQ, XieJX, et al. MAOA suppresses the growth of gastric cancer by interacting with NDRG1 and regulating the Warburg effect through the PI3K/AKT/mTOR pathway. Cell Oncol (Dordr). 2023;46:1429-1444.

[193] GaurS, GrossME, LiaoCP, Qian B, ShihJC. Effect of Monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells. Prostate. 2019;79:667-677.

[194] WangK, LuoJ, YehS, et al. The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer. Nat Commun. 2020;11:2689.

[195] WangYC, WangX, YuJ, et al. Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy. Nat Commun. 2021;12:3530.

[196] LapierreJA, GearyLA, JangJK, Epstein AL, HongF, ShihJC. Deletion of monoamine oxidase A in a prostate cancer model enhances anti-tumor immunity through reduced immune suppression. Biochem Biophys Res Commun. 2022;634:100-107.

[197] GrossME, AgusDB, DorffTB, et al. Phase 2 trial of monoamine oxidase inhibitor phenelzine in biochemical recurrent prostate cancer. Prostate Cancer Prostatic Dis. 2021;24:61-68.

[198] JayachandranP, Battaglin F, StrelezC, et al. Breast cancer and neurotransmitters: emerging insights on mechanisms and therapeutic directions. Oncogene. 2023;42:627-637.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.