Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Downregulation of CCKBR Expression Inhibits the Proliferation of Gastric Cancer Cells, Revealing a Potential Target for Immunotoxin Therapy

Author(s): Meng Li, Jiang Chang, Honglin Ren, Defeng Song, Jian Guo, Lixiong Peng, Xiaoshi Zhou, Ke Zhao, Shiying Lu, Zengshan Liu and Pan Hu*

Volume 22, Issue 3, 2022

Published on: 17 March, 2022

Page: [257 - 268] Pages: 12

DOI: 10.2174/1568009622666220106113616

Price: $65

Abstract

Background: Increased CCKBR expression density or frequency has been reported in many neoplasms.

Objective: We aimed to investigate whether CCKBR drives the growth of gastric cancer (GC) and its potential as a therapeutic target of immunotoxins.

Methods: A lentiviral interference system was used to generate CCKBR-knockdown gastric cancer cells. Cell Counting Kit-8 and clonogenic assays were used to evaluate cell proliferation. Woundhealing and cell invasion assays were performed to evaluate cell mobility. Cell cycle was analyzed by flow cytometry. Tumor growth in vivo was investigated using a heterologous tumor transplantation model in nude mice. In addition, we generated the immunotoxin FQ17P and evaluated the combining capacity and tumor cytotoxicity of FQ17P in vitro.

Results: Stable downregulation of CCKBR expression resulted in reduced proliferation, migration and invasion of BGC-823 and SGC-7901 cells. The impact of CCKBR on gastric cancer cells was further verified through CCKBR overexpression studies. Downregulation of CCKBR expression also inhibited the growth of gastric tumors in vivo. Furthermore, FQ17P killed CCKBR-overexpressing GC cells by specifically binding to CCKBR on the tumor cell surface.

Conclusion: The CCKBR protein drives the growth, migration, and invasion of gastric cancer cells, and it might be a promising target for immunotoxin therapy based on its aberrant expression, functional binding interactions with gastrin, and subsequent internalization.

Keywords: CCKBR, ribonucleic acid interference, gastric cancer proliferation, targeted therapy, immunotoxin, FQ17P.

« Previous
Graphical Abstract

[1]
Berna, M.J.; Jensen, R.T. Role of CCK/gastrin receptors in gastrointestinal/metabolic diseases and results of human studies using gastrin/CCK receptor agonists/antagonists in these diseases. Curr. Top. Med. Chem., 2007, 7(12), 1211-1231.
[http://dx.doi.org/10.2174/156802607780960519] [PMID: 17584143]
[2]
Dufresne, M.; Seva, C.; Fourmy, D. Cholecystokinin and gastrin receptors. Physiol. Rev., 2006, 86(3), 805-847.
[http://dx.doi.org/10.1152/physrev.00014.2005] [PMID: 16816139]
[3]
Baldwin, G.S.; Shulkes, A. CCK receptors and cancer. Curr. Top. Med. Chem., 2007, 7(12), 1232-1238.
[http://dx.doi.org/10.2174/156802607780960492] [PMID: 17584144]
[4]
Reubi, J.C. Targeting CCK receptors in human cancers. Curr. Top. Med. Chem., 2007, 7(12), 1239-1242.
[http://dx.doi.org/10.2174/156802607780960546] [PMID: 17584145]
[5]
Aly, A.; Shulkes, A.; Baldwin, G.S. Gastrins, cholecystokinins and gastrointestinal cancer. Biochim. Biophys. Acta, 2004, 1704(1), 1-10.
[http://dx.doi.org/10.1016/j.bbcan.2004.01.004] [PMID: 15238241]
[6]
Reubi, J.C.; Waser, B.; Läderach, U.; Stettler, C.; Friess, H.; Halter, F.; Schmassmann, A. Localization of cholecystokinin A and cholecystokinin B-gastrin receptors in the human stomach. Gastroenterology, 1997, 112(4), 1197-1205.
[http://dx.doi.org/10.1016/S0016-5085(97)70131-8] [PMID: 9098003]
[7]
Quattrone, A.; Dewaele, B.; Wozniak, A.; Bauters, M.; Vanspauwen, V.; Floris, G.; Schöffski, P.; Chibon, F.; Coindre, J.M.; Sciot, R.; Debiec-Rychter, M. Promoting role of cholecystokinin 2 receptor (CCK2R) in gastrointestinal stromal tumour pathogenesis. J. Pathol., 2012, 228(4), 565-574.
[http://dx.doi.org/10.1002/path.4071] [PMID: 22786615]
[8]
Ashurst, H.L.; Varro, A.; Dimaline, R. Regulation of mammalian gastrin/CCK receptor (CCK2R) expression in vitro and in vivo. Exp. Physiol., 2008, 93(2), 223-236.
[http://dx.doi.org/10.1113/expphysiol.2007.040683] [PMID: 17933865]
[9]
Noble, F.; Roques, B.P. CCK-B receptor: Chemistry, molecular biology, biochemistry and pharmacology. Prog. Neurobiol., 1999, 58(4), 349-379.
[http://dx.doi.org/10.1016/S0301-0082(98)00090-2] [PMID: 10368033]
[10]
Edkins, J.S. The chemical mechanism of gastric secretion. J. Physiol., 1906, 34(1-2), 133-144.
[http://dx.doi.org/10.1113/jphysiol.1906.sp001146] [PMID: 16992839]
[11]
Jensen, R.T. Consequences of long-term proton pump blockade: Insights from studies of patients with gastrinomas. Basic Clin. Pharmacol. Toxicol., 2006, 98(1), 4-19.
[http://dx.doi.org/10.1111/j.1742-7843.2006.pto_378.x] [PMID: 16433886]
[12]
Lehmann, F.; Hildebrand, P.; Beglinger, C. New molecular targets for treatment of peptic ulcer disease. Drugs, 2003, 63(17), 1785-1797.
[http://dx.doi.org/10.2165/00003495-200363170-00002] [PMID: 12921485]
[13]
Dockray, G.J. Clinical endocrinology and metabolism. Gastrin. Best Pract. Res. Clin. Endocrinol. Metab., 2004, 18(4), 555-568.
[http://dx.doi.org/10.1016/j.beem.2004.07.003] [PMID: 15533775]
[14]
Smith, J.P.; Fantaskey, A.P.; Liu, G.; Zagon, I.S. Identification of gastrin as a growth peptide in human pancreatic cancer. Am. J. Physiol., 1995, 268(1 Pt 2), R135-R141.
[http://dx.doi.org/10.1152/ajpregu.1995.268.1.R135] [PMID: 7840313]
[15]
Matters, G.L.; Harms, J.F.; McGovern, C.O.; Jayakumar, C.; Crepin, K.; Smith, Z.P.; Nelson, M.C.; Stock, H.; Fenn, C.W.; Kaiser, J.; Kester, M.; Smith, J.P. Growth of human pancreatic cancer is inhibited by down-regulation of gastrin gene expression. Pancreas, 2009, 38(5), e151-e161.
[http://dx.doi.org/10.1097/MPA.0b013e3181a66fdc] [PMID: 19465883]
[16]
Matters, G.L.; McGovern, C.; Harms, J.F.; Markovic, K.; Anson, K.; Jayakumar, C.; Martenis, M.; Awad, C.; Smith, J.P. Role of endogenous cholecystokinin on growth of human pancreatic cancer. Int. J. Oncol., 2011, 38(3), 593-601.
[http://dx.doi.org/10.3892/ijo.2010.886] [PMID: 21186400]
[17]
Watson, S.A.; Michaeli, D.; Grimes, S.; Morris, T.M.; Robinson, G.; Varro, A.; Justin, T.A.; Hardcastle, J.D. Gastrimmune raises antibodies that neutralize amidated and glycine-extended gastrin-17 and inhibit the growth of colon cancer. Cancer Res., 1996, 56(4), 880-885.
[PMID: 8631028]
[18]
Müerköster, S.; Isberner, A.; Arlt, A.; Witt, M.; Reimann, B.; Blaszczuk, E.; Werbing, V.; Fölsch, U.R.; Schmitz, F.; Schäfer, H. Gastrin suppresses growth of CCK2 receptor expressing colon cancer cells by inducing apoptosis in vitro and in vivo. Gastroenterology, 2005, 129(3), 952-968.
[http://dx.doi.org/10.1053/j.gastro.2005.06.059] [PMID: 16143134]
[19]
Sebens Müerköster, S.; Rausch, A.V.; Isberner, A.; Minkenberg, J.; Blaszczuk, E.; Witt, M.; Fölsch, U.R.; Schmitz, F.; Schäfer, H.; Arlt, A. The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-kappa B inhibition. Oncogene, 2008, 27(8), 1122-1134.
[http://dx.doi.org/10.1038/sj.onc.1210728] [PMID: 17704804]
[20]
Prince, H.M.; Martin, A.G.; Olsen, E.A.; Fivenson, D.P.; Duvic, M. Denileukin diftitox for the treatment of CD25 low-expression mycosis fungoides and Sézary syndrome. Leuk. Lymphoma, 2013, 54(1), 69-75.
[http://dx.doi.org/10.3109/10428194.2012.706286] [PMID: 22738414]
[21]
Kowalski, M.; Guindon, J.; Brazas, L.; Moore, C.; Entwistle, J.; Cizeau, J.; Jewett, M.A.; MacDonald, G.C. A phase II study of oportuzumab monatox: An immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guérin. J. Urol., 2012, 188(5), 1712-1718.
[http://dx.doi.org/10.1016/j.juro.2012.07.020] [PMID: 22998907]
[22]
Fino, K.K.; Matters, G.L.; McGovern, C.O.; Gilius, E.L.; Smith, J.P. Downregulation of the CCK-B receptor in pancreatic cancer cells blocks proliferation and promotes apoptosis. Am. J. Physiol. Gastrointest. Liver Physiol., 2012, 302(11), G1244-G1252.
[http://dx.doi.org/10.1152/ajpgi.00460.2011] [PMID: 22442157]
[23]
Chang, J.; Liu, Z-S.; Song, D-F.; Li, M.; Zhang, S.; Zhao, K.; Guan, Y.T.; Ren, H.L.; Li, Y.S.; Zhou, Y.; Liu, X.L.; Lu, S.Y.; Hu, P. Cholecystokinin type 2 receptor in colorectal cancer: Diagnostic and therapeutic target. J. Cancer Res. Clin. Oncol., 2020, 146(9), 2205-2217.
[http://dx.doi.org/10.1007/s00432-020-03273-z] [PMID: 32488497]
[24]
Chandrashekar, D.S.; Bashel, B.; Balasubramanya, S.A.H.; Creighton, C.J.; Ponce-Rodriguez, I.; Chakravarthi, B.V.S.K.; Varambally, S. UALCAN: A Portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia, 2017, 19(8), 649-658.
[http://dx.doi.org/10.1016/j.neo.2017.05.002] [PMID: 28732212]
[25]
Feng, X-L.; Liu, Z-S.; Liu, X-L.; Lu, S-Y.; Li, Y-S.; Hu, P.; Yan, D.M.; Tong, W.H.; Wang, Q.; Zhou, Y.; Jin, W.; Ding, Y.X.; Gai, D.X.; Ren, H.L. Establishment of a three-step purification scheme for a recombinant protein rG17PE38 and its characteristics identification. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2015, 981-982, 48-56.
[http://dx.doi.org/10.1016/j.jchromb.2015.01.008] [PMID: 25600055]
[26]
Hu, P.; Zhang, S.; Lu, S.Y.; Li, M.; Chang, J.; Wang, M.Y.; Li, C.; Zhao, K.; Guan, Y.T.; Zhang, Y.Y.; Li, Y.S.; Zhou, Y.; Liu, Z.S.; Bai, O.; Ren, H.L. An efficient scheme for purification of a novel recombinant immunotoxin, rCCK8PE38, for anti-tumour experiments. Biomed. Chromatogr., 2018, 32(6), e4197.
[http://dx.doi.org/10.1002/bmc.4197] [PMID: 29359465]
[27]
Smith, J.P.; Hamory, M.W.; Verderame, M.F.; Zagon, I.S. Quantitative analysis of gastrin mRNA and peptide in normal and cancerous human pancreas. Int. J. Mol. Med., 1998, 2(3), 309-315.
[http://dx.doi.org/10.3892/ijmm.2.3.309] [PMID: 9855703]
[28]
Mjønes, P.; Nordrum, I.S.; Sørdal, Ø.; Sagatun, L.; Fossmark, R.; Sandvik, A.; Waldum, H.L. Expression of the cholecystokinin-b receptor in neoplastic gastric cells. Horm. Cancer, 2018, 9(1), 40-54.
[http://dx.doi.org/10.1007/s12672-017-0311-8] [PMID: 28980157]
[29]
Rozengurt, E.; Sinnett-Smith, J.; Kisfalvi, K. Crosstalk between Insulin/IGF-1 and GPCR signaling systems: A novel target for the anti-diabetic drug metformin in pancreatic cancer. Clin. Cancer Res., 2010, 16, 2505-2511.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-2229] [PMID: 20388847]
[30]
Young, S.H.; Rozengurt, E. Crosstalk between insulin receptor and G protein-coupled receptor signaling systems leads to Ca2+ oscillations in pancreatic cancer PANC-1 cells. Biochem. Biophys. Res. Commun., 2010, 401(1), 154-158.
[http://dx.doi.org/10.1016/j.bbrc.2010.09.036] [PMID: 20849815]
[31]
Chao, C.; Han, X.; Ives, K.; Park, J.; Kolokoltsov, A.A.; Davey, R.A.; Moyer, M.P.; Hellmich, M.R. CCK2 receptor expression transforms non-tumorigenic human NCM356 colonic epithelial cells into tumor forming cells. Int. J. Cancer, 2010, 126(4), 864-875.
[http://dx.doi.org/10.1002/ijc.24845] [PMID: 19697327]
[32]
Clerc, P.; Leung-Theung-Long, S.; Wang, T.C.; Dockray, G.J.; Bouisson, M.; Delisle, M-B.; Vaysse, N.; Pradayrol, L.; Fourmy, D.; Dufresne, M. Expression of CCK2 receptors in the murine pancreas: Proliferation, transdifferentiation of acinar cells, and neoplasia. Gastroenterology, 2002, 122(2), 428-437.
[http://dx.doi.org/10.1053/gast.2002.30984] [PMID: 11832457]
[33]
Jin, G.; Ramanathan, V.; Quante, M.; Baik, G.H.; Yang, X.; Wang, S.S.W.; Tu, S.; Gordon, S.A.; Pritchard, D.M.; Varro, A.; Shulkes, A.; Wang, T.C. Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice. J. Clin. Invest., 2009, 119(9), 2691-2701.
[http://dx.doi.org/10.1172/JCI38918] [PMID: 19652364]
[34]
Singh, P.; Velasco, M.; Given, R.; Wargovich, M.; Varro, A.; Wang, T.C. Mice overexpressing progastrin are predisposed for developing aberrant colonic crypt foci in response to AOM. Am. J. Physiol. Gastrointest. Liver Physiol., 2000, 278(3), G390-G399.
[http://dx.doi.org/10.1152/ajpgi.2000.278.3.G390] [PMID: 10712258]
[35]
Pradeep, A.; Sharma, C.; Sathyanarayana, P.; Albanese, C.; Fleming, J.V.; Wang, T.C.; Wolfe, M.M.; Baker, K.M.; Pestell, R.G.; Rana, B. Gastrin-mediated activation of cyclin D1 transcription involves beta-catenin and CREB pathways in gastric cancer cells. Oncogene, 2004, 23(20), 3689-3699.
[http://dx.doi.org/10.1038/sj.onc.1207454] [PMID: 15116100]
[36]
Song, D.H.; Rana, B.; Wolfe, J.R.; Crimmins, G.; Choi, C.; Albanese, C.; Wang, T.C.; Pestell, R.G.; Wolfe, M.M. Gastrin-induced gastric adenocarcinoma growth is mediated through cyclin D1. Am. J. Physiol. Gastrointest. Liver Physiol., 2003, 285(1), G217-G222.
[http://dx.doi.org/10.1152/ajpgi.00516.2002] [PMID: 12606305]
[37]
Zhukova, E.; Sinnett-Smith, J.; Wong, H.; Chiu, T.; Rozengurt, E. CCK(B)/gastrin receptor mediates synergistic stimulation of DNA synthesis and cyclin D1, D3, and E expression in Swiss 3T3 cells. J. Cell. Physiol., 2001, 189(3), 291-305.
[http://dx.doi.org/10.1002/jcp.10018] [PMID: 11748587]
[38]
Bao, Z.; Xu, X.; Liu, Y.; Chao, H.; Lin, C.; Li, Z.; You, Y.; Liu, N.; Ji, J. CBX7 negatively regulates migration and invasion in glioma via Wnt/β-catenin pathway inactivation. Oncotarget, 2017, 8(24), 39048-39063.
[http://dx.doi.org/10.18632/oncotarget.16587] [PMID: 28388562]
[39]
Liu, C-C.; Cai, D-L.; Sun, F.; Wu, Z-H.; Yue, B.; Zhao, S-L.; Wu, X.S.; Zhang, M.; Zhu, X.W.; Peng, Z.H.; Yan, D.W. FERMT1 mediates epithelial-mesenchymal transition to promote colon cancer metastasis, via modulation of β-catenin transcriptional activity. Oncogene, 2017, 36(13), 1779-1792.
[http://dx.doi.org/10.1038/onc.2016.339] [PMID: 27641329]
[40]
Chau, I.; Cunningham, D.; Russell, C.; Norman, A.R.; Kurzawinski, T.; Harper, P.; Harrison, P.; Middleton, G.; Daniels, F.; Hickish, T.; Prendeville, J.; Ross, P.J.; Theis, B.; Hull, R.; Walker, M.; Shankley, N.; Kalindjian, B.; Murray, G.; Gillbanks, A.; Black, J. Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: Results from two randomised controlled trials. Br. J. Cancer, 2006, 94(8), 1107-1115.
[http://dx.doi.org/10.1038/sj.bjc.6603058] [PMID: 16622436]
[41]
Meyer, T.; Caplin, M.E.; Palmer, D.H.; Valle, J.W.; Larvin, M.; Waters, J.S.; Coxon, F.; Borbath, I.; Peeters, M.; Nagano, E.; Kato, H. A phase Ib/IIa trial to evaluate the CCK2 receptor antagonist Z-360 in combination with gemcitabine in patients with advanced pancreatic cancer. Eur. J. Cancer, 2010, 46(3), 526-533.
[http://dx.doi.org/10.1016/j.ejca.2009.11.004] [PMID: 20006921]
[42]
Calatayud, S.; Alvarez, A.; Víctor, V.M. Gastrin: An acid-releasing, proliferative and immunomodulatory peptide? Mini Rev. Med. Chem., 2010, 10(1), 8-19.
[http://dx.doi.org/10.2174/138955710791112532] [PMID: 20380639]
[43]
Kreitman, R.J.; Dearden, C.; Zinzani, P.L.; Delgado, J.; Karlin, L.; Robak, T.; Gladstone, D.E.; le Coutre, P.; Dietrich, S.; Gotic, M.; Larratt, L.; Offner, F.; Schiller, G.; Swords, R.; Bacon, L.; Bocchia, M.; Bouabdallah, K.; Breems, D.A.; Cortelezzi, A.; Dinner, S.; Doubek, M.; Gjertsen, B.T.; Gobbi, M.; Hellmann, A.; Lepretre, S.; Maloisel, F.; Ravandi, F.; Rousselot, P.; Rummel, M.; Siddiqi, T.; Tadmor, T.; Troussard, X.; Yi, C.A.; Saglio, G.; Roboz, G.J.; Balic, K.; Standifer, N.; He, P.; Marshall, S.; Wilson, W.; Pastan, I.; Yao, N.S.; Giles, F. Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia. Leukemia, 2018, 32(8), 1768-1777.
[http://dx.doi.org/10.1038/s41375-018-0210-1] [PMID: 30030507]
[44]
Reubi, J.C.; Mäcke, H.R.; Krenning, E.P. Candidates for peptide receptor radiotherapy today and in the future. J. Nucl. Med., 2005, 46(Suppl. 1), 67S-75S.
[PMID: 15653654]
[45]
Laverman, P.; Béhé, M.; Oyen, W.J.G.; Willems, P.H.G.M.; Corstens, F.H.M.; Behr, T.M.; Boerman, O.C. Two technetium-99m-labeled cholecystokinin-8 (CCK8) peptides for scintigraphic imaging of CCK receptors. Bioconjug. Chem., 2004, 15(3), 561-568.
[http://dx.doi.org/10.1021/bc034208w] [PMID: 15149184]
[46]
Song, J.; Ren, H.; Li, Y.; Xu, J.; Kong, H.; Tong, W.; Zhou, Y.; Gao, S.; Liu, Y.; Hui, Q.; Peng, Q.; Lu, S.; Liu, Z. rG17PE38, a novel immunotoxin target to gastric cancer with overexpressed CCK-2R. J. Drug Target., 2013, 21(4), 375-382.
[http://dx.doi.org/10.3109/1061186X.2012.757770] [PMID: 23311704]
[47]
Feng, X-L.; Liu, X-L.; Lu, S-Y.; Ren, H-L.; Li, Y-S.; Hu, P.; Wang, Q.; Tong, W.; Yan, D.M.; Zhou, Y.; Zhang, S.; Jin, W.; Liu, Z.S. Expression, purification and characterization of recombinant toxins consisting of truncated gastrin 17 and pseudomonas exotoxin. Protein Pept. Lett., 2015, 22(2), 193-201.
[http://dx.doi.org/10.2174/0929866521666141028214723] [PMID: 25353354]
[48]
Vlachostergios, P.J.; Jakubowski, C.D.; Niaz, M.J.; Lee, A.; Thomas, C.; Hackett, A.L.; Patel, P.; Rashid, N.; Tagawa, S.T. Antibody-drug conjugates in bladder cancer. Bladder Cancer, 2018, 4(3), 247-259.
[http://dx.doi.org/10.3233/BLC-180169] [PMID: 30112436]

Rights & Permissions Print Cite
Article Metrics
32
1
© 2024 Bentham Science Publishers | Privacy Policy