Abstract
In the present review we discuss a central role for substance P (SP) in carcinogenesis. We suggest that one mechanism to induce mitogenesis of tumor cells is the activation of neurokinin-1 receptor (NK1R) through SP, linking cancer promotion and progression to a neurokinin-mediated environment. After reviewing the role of both SP and its receptor NK1R in normal and neoplastic cells we propose the use of neurokinin-1 receptor antagonists as a novel and promising approach for treating patients with cancer.
Similar content being viewed by others
References
Hahn WC, Weinberg RA: Mechanisms of disease: rules for making human tumor cells. N Engl J Med 347: 1593–1603, 2002
Rollandy I, Dreux C, Imhoff V, Rossignol B: Importance of the presence of the N-terminal tripeptide of substance P for the stimulation of phosphatidylinositol metabolism in rat parotid gland: a possible activation of phospholipases C and D. Neuropeptides 13: 175–185, 1989
Pradier L, Heuillet E, Hubert JP, Laville M, Le Guern S, Doble A: J Neurochem 61: 1850–1858, 1993
Luo W, Sharif TR, Sharif M: Substance P-induced mitogenesis in human astrocytoma cells correlates with activation of the mitogen-activated protein kinase signaling pathway. Cancer Res 56:4983–4991, 1996
DeFea KA, Zalevsky J, Thoma MS, De'ry O, Mullins RD, Bunnett NW: Beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J Cell Biol 148: 1267–1282, 2000
Van den Broeck J, Torfs H, Poels J, Van Poyer W, Swinnen E, Ferket K, De Loof A: Tachykinin-like peptides and their receptors. A review. Ann NY Acad Sci 897:374–387, 1999
Patacchini R, Maggi CA: Peripheral tachykinin receptors as targets for new drugs. Eur J Pharmacol 429(1–3): 13–21, 2001
Khawaja AM, Rogers DF: Tachykinins: receptor to effector. Int J Biochem Cell Biol 28: 721–738, 1996
Quartara L, Maggi CA: The tachykinin NK1 receptor. Part II: distribution and pathophysiological roles. Neuropeptides 32:1–49, 1998
Guo CJ, Lai JP, Luo HM, Douglas SD, Ho WZ: Substance P up-regulates macrophage inflammatory protein-1beta expression in human T lymphocytes. J Neuroimmunol 131(1–2): 160–167, 2002
Fiebich BL, Schleicher S, Butcher RD, Craig A, Lieb K: The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-kappa B. J Immunol 165(10): 5606–5611, 2000
Castagliuolo I, Valenick L, Liu J, Pothoulakis C: Epidermal growth factor receptor transactivation mediates substance P-induced mitogenic responses in U-373 MG cells. J Biol Chem 275: 26545–26550, 2000
McGillis JP, Mitsuhashi M, Payan DG: Immunomodulation by tachykinin neuropeptides. Ann NY Acad Sci 594:85–94, 1990
Goetzl EJ, Sreedharan SP: Mediators of communication and adaptation in the neuroendocrine and immune systems. FASEB J 6(9):2646–2652, 1992
Lambrecht BN: Immunologists getting nervous: neuropeptides, dendritic cells and T cell activation. Respir Res 2(3):133–138, 2001
Rozengurt E: Neuropeptides as growth factors for normal and cancerous cells. Trends Endocrinol Metab 13(3):128–134, 2002
von Euler US, Gaddum JH: An unidentified depressor substance in certain tissue extracts. J Physiol 72:74–87, 1931
DeVane CL: Substance P: a new era, a new role. Pharmacotherapy 21(9): 1061–1069, 2001
Culman J, Unger T: Central tachykinins: mediators of defence reaction and stress reactions. Can J Physiol Pharmacol 73(7):885–891, 1995
De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP: Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392(6674):394–397, 1998
Mantyh PW: Substance P and the inflammatory and immune response. Ann NY Acad Sci 632:263–271, 1991
Harrison S, Geppetti P: Substance P. Int J Biochem Cell Biol 33:555–576, 2001
Chahl LA, Ladd RJ: Local oedema and general excitation of cutaneous sensory receptors produced by electrical stimulation of the saphenous nerve in the rat. Pain 2:25–34, 1976
Lembeck F, Holzer P: Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation. Naunyn-Schmiedeberg's Arch Pharmacol 310:175–183, 1979
Furness J, Papka RE, Della NG, Costa M, Eskay RL: Substance P-like immunoreactivity in nerves associated with the vascular system of guinea-pigs Neuroscience 7:447–459, 1982
Lundberg JM, Brodin E, Hua X, Saria A. Vascular permeability changes and smooth muscle contraction in relation to capsaicin-sensitive substance P afferents in the guinea-pig. Acta Physiol Scand 120:217–227, 1984
Pascual DW, Xu-Amano J, Kiyono H, McGhee JR, Bost KL: Substance P acts directly upon cloned B Lymphoma cells to enhace IgA and IgM production. J Immunol 146:2130–2136, 1991
Feistritzer C, Clausen J, Sturn DH, Djanani A, Gunsilius E, Wiedermann CJ, Kahler CM: Natural killer cell functions mediated by the neuropeptide substance P. Regul Pep 116:119–126, 2003
Lieb K, Fiebich BL, Berger M, Bauer J, Schulze-Osthoff K: The neuropeptide substance P activates transcription factors NF.kB and kB-dependent gene expression in human astrocytoma cells. J Immunol 159:4952–4958, 1997
Muńoz M, Pérez A, Rosso M, Zamarriego C, Rosso R: Antitumoural action of NK1 receptor antagonist L-733,060 on human melanoma cell lines. Melanoma Res 14:183–188, 2004b
Walsh DT, Weg VB, Williams TJ, Nourshargh S: Substance P induced inflammatory responses in guinea-pig skin: the effect of specific NK1 receptor antagonists and the role of endogenous mediators. Br J Pharmacol 114:1343–1350, 1995
Weinstock JV, Blum A, Walden J, Walden T: Eosinophils from granulomas in murine Schistosomiasis mansoni produce SP. J Immunology 141:961–966, 1998
Cook GA, Elliott D, Metwali A, Blu AM, Sandor M, Lynch R, Weinstock JV: Molecular evidence that granuloma T lymphocytes in murine Schistosomiasis mansoni express an authentic SP (NK1) receptor. J Immunology 152:1830–1835, 1994
Keranen U, Jarvinen H, Kiviluoto T, Kivilaakso E, Soinila S: Substance P and VIP-immunoreactive innervation in normal and inflamed pouches after restorative proctocolectomy for ulcerative colitis. Dig Dis Sci 41:1658–1664, 1996
Keranen U, Jarvinen H, Karkkaine P, Kiviluoto T, Kivilaakso E, Soinila S: Substance P–-an underlying factor for pouchitis?. Prospective study of substance P and VIP-immunoreactive innervation and mast cells. Dig Dis Sci 41:1665–1671, 1996
Payan DG, Brewster DR, Missirian-Bastian A, Goetzl EJ: Substance P recognition of a subset of human T lymphocytes. J Clin Invest 74:1532–1539, 1984
Hepler JR, Gilman AC: G proteins. Trends Biochem Sci 17: 383–387, 1992
Clapham D, Neer EJ: New roles: G protein β γ -dimers in transmembrane signalling. Nature 365: 406, 1993
Horstmann S, Kahle PJ, Borasio GD: Inhibitors of p38 mitogen-activated protein kinase promote neuronal survival in vitro J. Neurosci Res 52: 483–490, 1998
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270: 1326–1331, 1995
Daaka Y, Luttrell LM, Lefkowitz RJ: Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A. Nature 390: 88–91, 1997
DeFea KA, Vaughn ZD, O'Bryan EM, Nishijima D, Dery O, Bunnett NW: The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta-arrestin-dependent scaffolding complex. Proc Natl Acad Sci USA 97(20):11086–11091, 2000
Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, Lin F, Kawakatsu H, Owada K, Luttrell DK, Caron MG, Lefkowitz RJ : Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science 283: 655–661, 1999
van Biesen T, Hawes BE, Raymond JR, Luttrell LM, Koch WJ, Lefkowitz RJ: G(o)-protein alpha-subunits activate mitogen-activated protein kinase via a novel protein kinase C-dependent mechanism. J Biol Chem 271(3):1266–1269, 1996
Ignatova EG, Belcheva MM, Bohn LM, Neuman MC, Coscia CJ: Requirement of receptor internalization for opioid stimulation of mitogen-activated protein kinase: biochemical and immunofluorescence confocal microscopic evidence. J Neurosci 19: 56–63, 1999
Vögler O, Nolte B, Voss M, Schmidt M, Jakobs KH, van Koppen CJ: Regulation of muscarinic acetylcholine receptor sequestration and function by beta-arrestin. J Biol Chem 274: 12333–12338, 1999
Koon HW, Zhao D, Na X, Moyer MP, Pothoulakis C: Metalloproteinases and Transforming Growth Factor-α Mediate Substance P-induced Mitogen-activated Protein Kinase Activation and Proliferation in Human Colonocytes. J Biol Chem 279: 45519–45527, 2004
Parma J, Duprey L, Van Sande J, Cochaux P, Gervy C, Mochel J, Dumont J, Vassart G: Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365: 649–651, 1993
Daub H, Wallasch C, Lankenau A, Herrlich A, Ullrich A: Signal characteristics of G protein-transactivated EGF receptor. EMBO J 16 7032–7044, 1997
Friess H, Zhu Z, Liard V, Shi X, Shrikhande SV, Wang L, Lieb K, Korc M, Palma C, Zimmermann A, Reubi JC, Buchler MW: Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer. Lab Invest 83:731–742, 2003
Palma C, Nardelli F, Manzini S, Maggi CA: Substance P activates responses correlated with tumour growth in human glioma cells line bearing tachykinin NK1 receptors. Br J Cancer 79:236–243, 1999
Muńoz M, Pérez A, Coveńas R, Rosso M, Castro E: Antitumoural action of L-733,060 on neuroblastoma and glioma cell lines. Arch Ital Biol 142:105–112, 2004a
Singh D, Joshi DD, Hameed M, Qian J, Gascon P, Maloof PB, Mosenthal A, Rameshwar P: Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis. Proc Natl Acad Sci USA 97 388–393, 2000
Sitohy B, El Salhy M: Changes in the colonic enteric nervous system in rats with chemically induced colon dysplasia and carcinoma. Acta Oncol 41:543–549, 2002
Payan DG, Brewster DR, Goetzl EJ: Specific stimulation of human T lymphocytes by substance P. J Immunol 131:1613–1615, 1983
Nilsson J, von Euler AM, Dalsgaard CJ: Stimulation of connective tissue cell growth by substance P and substance K. Nature 315:61–63, 1985
Lotz M, Carson DA, Vaughan JH: Substance P activation of rheumatoid synoviocytes: neural pathway in pathogenesis of arthritis. Science 235:893–895, 1987
Ziche M, Morbidelli L, Pacini M, Dolara P, Maggi CA: NK1-receptors mediate the proliferative response of human fibroblasts to tachykinins. Br J Pharmacol 100:11–14, 1990
Sharif TR, Luo W, Houghron PJ, Sharif M. Substance K peptide induces mitogenesis by activating the mitogen-activated protein kinase signalling pathway through the substance P receptor (NK-1 subtype) in human astrocytoma. Cell Pharmacol 3:441–449, 1996
Muńoz M, Rosso M, Pérez A, Coveńas R, Rosso R, Zamarriego C, Piruat JI: The NK1 receptor is involved in the antitumoural action of L-733,060 and in the mitogenic action of substance P on neuroblastoma and glioma cell lines. Neuropeptides 39(4): 427–32, 2005a
Muńoz M, Rosso M, Pérez A, Coveńas R, Rosso R, Zamarriego C, Soult JA, Montero I. Antitumoural action of the neurokinin-1-receptor antagonist L-733,060 and mitogenic action of substance P on human retinoblastoma cell lines. Invest Ophthalmol Vis Sci 46:2567–2570, 2005b
Fowler CJ, Brannstrom G: Substance P enhances forskolin-stimulated cyclic AMP production in human UC11MG astrocytoma cells. Methods Find Exp Clin Pharmacol 16:21–28, 1994
Globus M, Smith MJ, Vethamany-Globus S: Evidence supporting a mitogenic role for substance P in amphibian limb regeneration. Ann NY Acad Sci 632:396–399, 1991
Salo E, Baguna T: Stimulation of cellular proliferation and differentiation in the intact and regenerating planarian Dugesia(G) tigrina by the neuropeptide substance P. J Exp Zool 237:129–135, 1986
Lee CM, Kum W, Cockram CS, Teoh R, Young JD: Functional substance P receptors on a human astrocytoma cell line (U-373 MG). Brain Res 488:328–331, 1989
Eistetter HR, Mills A, Brewster R, Alouani S, Rambosson C, Kawashima E: Functional characterization of neurokinin-1 receptors on human U373MG astrocytoma cells. Glia 6:89–95, 1992
Bang R, Sass G, Kiemer AK, Vollmar AM, Neuhuber WL, Tiegs G: Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury. J Pharmacol Exp Ther 305: 31–39, 2003
Rupniak NM, Carlson E, Boyce S, Webb JK, Hill RG: Enantioselective inhibition of the formalin paw late phase by the NK1 receptor antagonist L-733,060 in gerbils. Pain 67:189–195, 1996
Muńoz M, Rosso M, Coveńas R, Soult JA. Antitumoural action of neurokinin-1 receptor antagonists on human brain cancer cell lines. In: Brain Cancer: Therapy and Surgical Interventions 2006 (in press)
Lang K, Drell TL, Lindecke A, Niggemann B, Kaltschmidt C, Zaenker KS, Entschladen F: Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer 112:231–238, 2004
Woll PJ, Rozengurt E. Substance P, a potent bombesin antagonist in murine Swiss 3T3 cells, inhibits the growth of human small cell lung cancer cells in vitro. Proc Natl Acad Sci USA 35:1859–1863, 1998
Langdon S, Sethi T, Richie A, Muir M, Smyth J, Rozengurt E: Broad spectrum neuropeptide antagonists inhibit the growth of small cell lung cancer in vivo. Cancer Res 52:4554–4557, 1992
Reeve JG, Bleehen NM: Substance P induces apoptosis in lung cancer cell lines in vitro. Biochem Bioph Res Com 199:1313–1319, 1994
Seckl MJ, Higgins T, Wildmer F, Rozengurt E: Substance P: a novel potent inhibitor of signal transduction and growth in vitro and in vivo in small cell lung cancer cells. Cancer Res 57:51–54, 1997
Palma C, Bigioni M, Irrissuto C, Nardelli F, Maggi CA, Manzini S: Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft. Br J Cancer 82:480–487, 2000
Varty GB, Cohen-Williams ME, Hunter JC: The antidepressant-like effects of neurokinin NK1 receptor antagonists in a gerbil tail suspension test. Behav Pharmacol 14:87–95, 2003
Bang R, Biburger M, Neuhuber WL, Tiegs G: Neurokinin-1 Receptor Antagonists Protect Mice from CD95- and Tumor Necrosis Factor-α-Mediated Apoptotic. Liver Damage. J Pharmacol Exp Ther 308: 1174–1180, 2004
Goso C, Potier E, Manzini S, Szallasi A: Comparison of tachykinin NK1 receptors in human IM9 and U373 MG cells, using antagonist (FK888, +/−)-CP-96,345, and RP 67580) binding. Eur J Pharmacol 254:221–227, 1994
Bringold F, Serrano M: Tumor suppressors and oncogenes in cellular senescence. Exp Gerontol 35: 317–329, 2000
Bulavin DV, Demidov ON, Saito S, Kauraniemi P, Phillips C, Amundson SA, Ambrosino C, Sauter G, Nebreda AR, Anderson CW, Kallioniemi A, Fornace AJ Jr, Appella E: Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat Genet 31: 210–215, 2002
Ferbeyre GE, de Stanchina AW, Lin E, Querido ME, McCurrach GJ, Hannon S, Lowe SW: Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol 22: 3497–3508, 2002
Lin AW, Lowe SW: Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation. Proc Natl Acad Sci USA 98: 5025–5030, 2001
Serrano MA, Lin W, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593–602, 1997
Trost TM, Lausch EU, Fees SA, Schmitt S, Enklaar T, Reutzel D, Brixel LR, Schmidtke P, Maringer M, Schiffer IB, Heimerdinger CK, Hengstler JG, Fritz G, Bockamp EO, Prawitt D, Zabel BU, Spangenberg C: Premature senescence is a primary fail-safe mechanism of ERBB2-driven tumorigenesis in breast carcinoma cells. Cancer Res 65(3): 840–849, 2005
Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, Benguria A, Zaballos A, Flores JM, Barbacid M, Beach D, Serrano M: Tumour biology: senescence in premalignant tumours. Nature 436(7051): 642, 2005
Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, Stein H, Dorken B, Jenuwein T, Schmitt CA: Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436(7051): 660–665, 2005. Comment in: Nature 436(7051):636–637, 2005
Ding HF, Fisher DE: Induction of apoptosis in cancer: new therapeutic opportunities. Ann Med 34(6): 451–469, 2002
Hennig IM, Laissue JA, Horisberger U, Reubi JC: Substance-P receptors in human primary neoplasms: tumoral and vascular localization. Int J Cancer 61:786–792, 1995
Seegers HC, Hood VC, Kidd BL, Cruwys SC, Walsh DA: Enhancement of angiogenesis by endogenous substance P release and neurokinin-1 receptors during neurogenic inflammation. J Pharmacol Exp Ther 306(1): 8–12, 2003
Jacobs CM, Boldingh KA, Slagsvold HH, Thoresen GH, Paulsen RE: ERK2 Prohibits Apoptosis-induced Subcellular Translocation of Orphan Nuclear Receptor NGFI-B/TR3. Biol Chem 279: 50097–50101, 2004
Castro-Obregon S, Rao SV, del Rio G, Chen SF, Poksay KS, Rabizadeh S, Vesce S, Zhang XK, Swanson RA, Bredesen DE: Alternative, Nonapoptotic Programmed Cell Death. Mediation By Arrestin 2, Erk2, And Nur77. J Biol Chem 279:17543–17553, 2004
Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NM: Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281:1640–1645, 1998
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Esteban, F., Muñoz, M., González-Moles, M.A. et al. A role for substance P in cancer promotion and progression: a mechanism to counteract intracellular death signals following oncogene activation or DNA damage. Cancer Metastasis Rev 25, 137–145 (2006). https://doi.org/10.1007/s10555-006-8161-9
Issue Date:
DOI: https://doi.org/10.1007/s10555-006-8161-9