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Current Cancer Drug Targets

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

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Research Article

Blocking IL-6/GP130 Signaling Inhibits Cell Viability/Proliferation, Glycolysis, and Colony Forming Activity in Human Pancreatic Cancer Cells

Author(s): Xiang Chen, Jilai Tian, Gloria H. Su and Jiayuh Lin*

Volume 19, Issue 5, 2019

Page: [417 - 427] Pages: 11

DOI: 10.2174/1568009618666180430123939

Price: $65

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Abstract

Background: Elevated production of the pro-inflammatory cytokine interleukin-6 (IL-6) and dysfunction of IL-6 signaling promotes tumorigenesis and are associated with poor survival outcomes in multiple cancer types. Recent studies showed that the IL-6/GP130/STAT3 signaling pathway plays a pivotal role in pancreatic cancer development and maintenance.

Objective: We aim to develop effective treatments through inhibition of IL-6/GP130 signaling in pancreatic cancer.

Methods: The effects on cell viability and cell proliferation were measured by MTT and BrdU assays, respectively. The effects on glycolysis was determined by cell-based assays to measure lactate levels. Protein expression changes were evaluated by western blotting and immunoprecipitation. siRNA transfection was used to knock down estrogen receptor α gene expression. Colony forming ability was determined by colony forming cell assay.

Results: We demonstrated that IL-6 can induce pancreatic cancer cell viability/proliferation and glycolysis. We also showed that a repurposing FDA-approved drug bazedoxifene could inhibit the IL-6/IL-6R/GP130 complexes. Bazedoxifene also inhibited JAK1 binding to IL-6/IL-6R/GP130 complexes and STAT3 phosphorylation. In addition, bazedoxifene impeded IL-6 mediated cell viability/ proliferation and glycolysis in pancreatic cancer cells. Consistently, other IL-6/GP130 inhibitors SC144 and evista showed similar inhibition of IL-6 stimulated cell viability, cell proliferation and glycolysis. Furthermore, all three IL-6/GP130 inhibitors reduced the colony forming ability in pancreatic cancer cells.

Conclusion: Our findings demonstrated that IL-6 stimulates pancreatic cancer cell proliferation, survival and glycolysis, and supported persistent IL-6 signaling is a viable therapeutic target for pancreatic cancer using IL-6/GP130 inhibitors.

Keywords: IL-6/GP130 signaling, bazedoxifene, pancreatic cancer, cell viability, cell proliferation, glycolysis, colony forming.

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[1]
Rahib, L.; Smith, B.D.; Aizenberg, R.; Rosenzweig, A.B.; Fleshman, J.M.; Matrisian, L.M. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res., 2014, 74(11), 2913-2921.
[2]
Winter, J.M.; Brennan, M.F.; Tang, L.H.; D’Angelica, M.I.; DeMatteo, R.P.; Fong, Y.; Klimstra, D.S.; Jarnagin, W.R.; Allen, P.J. Survival after resection of pancreatic adenocarcinoma: results from a single institution over three decades. Ann. Surg. Oncol., 2012, 19(1), 169-175.
[3]
Al-Hajeili, M.; Azmi, A.S.; Choi, M. Nab-paclitaxel: potential for the treatment of advanced pancreatic cancer. OncoTargets Ther., 2014, 7, 187-192.
[4]
Moorcraft, S.Y.; Khan, K.; Peckitt, C.; Watkins, D.; Rao, S.; Cunningham, D.; Chau, I. FOLFIRINOX for locally advanced or metastatic pancreatic ductal adenocarcinoma: The Royal Marsden experience. Clin. Colorectal Cancer, 2014, 13(4), 232-238.
[5]
Von Hoff, D.D.; Ervin, T.; Arena, F.P. Chiorean, E.G.; Infante, J.; Moore, M.; Seay, T.; Tjulandin, S.A.; Ma, W.W.; Saleh, M.N.; Harris, M.; Reni, M.; Dowden, S.; Laheru, D.; Bahary, N.; Ramanathan, R.K.; Tabernero, J.; Hidalgo, M.; Goldstein, D.; Van Cutsem, E.; Wei, X.; Iglesias, J.; Renschler, M.F. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med., 2013, 369(18), 1691-1703.
[6]
Conroy, T.; Desseigne, F.; Ychou, M.; Bouche, O.; Guimbaud, R.; Becouarn, Y.; Adenis, A.; Raoul, J.L.; Gourgou-Bourgade, S.; de la Fouchardiere, C.; Bennouna, J.; Bachet, J.B.; Khemissa-Akouz, F.; Pere-Verge, D.; Delbaldo, C.; Assenat, E.; Chauffert, B.; Michel, P.; Montoto-Grillot, C.; Ducreux, M. Groupe Tumeurs Digestives of, U.; Intergroup, P. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med., 2011, 364(19), 1817-1825.
[7]
Hunter, C.A.; Jones, S.A. IL-6 as a keystone cytokine in health and disease. Nat. Immunol., 2015, 16(5), 448-457.
[8]
Hong, D.S.; Angelo, L.S.; Kurzrock, R. Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer, 2007, 110(9), 1911-1928.
[9]
Scheller, J.; Garbers, C.; Rose-John, S. Interleukin-6: From basic biology to selective blockade of pro-inflammatory activities. Semin. Immunol., 2014, 26(1), 2-12.
[10]
Wunderlich, F.T.; Strohle, P.; Konner, A.C.; Gruber, S.; Tovar, S.; Bronneke, H.S.; Juntti-Berggren, L.; Li, L.S.; van Rooijen, N.; Libert, C.; Berggren, P.O.; Bruning, J.C. Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab., 2010, 12(3), 237-249.
[11]
Yamasaki, K.; Taga, T.; Hirata, Y.; Yawata, H.; Kawanishi, Y.; Seed, B.; Taniguchi, T.; Hirano, T.; Kishimoto, T. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science, 1988, 241(4867), 825-828.
[12]
Lokau, J.; Garbers, C. Signal transduction of Interleukin-11 and Interleukin-6 α-Receptors. Receptors Clin. Investig., 2016, 3(2), e1190.
[13]
Jones, S.A.; Scheller, J.; Rose-John, S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J. Clin. Invest., 2011, 121(9), 3375-3383.
[14]
Garbers, C.; Aparicio-Siegmund, S.; Rose-John, S. The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Curr. Opin. Immunol., 2015, 34, 75-82.
[15]
Roxburgh, C.S.; McMillan, D.C. Therapeutics targeting innate immune/inflammatory responses through the interleukin-6/JAK/STAT signal transduction pathway in patients with cancer. Transl. Res., 2016, 167(1), 61-66.
[16]
Yao, X.; Huang, J.; Zhong, H.; Shen, N.; Faggioni, R.; Fung, M.; Yao, Y. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol. Ther., 2014, 141(2), 125-139.
[17]
Hu, B.; Zhang, K.; Li, S.; Li, H.; Yan, Z.; Huang, L.; Wu, J.; Han, X.; Jiang, W.; Mulatibieke, T. HIC1 attenuates invasion and metastasis by inhibiting the IL-6/STAT3 signalling pathway in human pancreatic cancer. Cancer Lett., 2016, 376(2), 387-398.
[18]
Xu, S.; Neamati, N. gp130: A promising drug target for cancer therapy. Expert Opin. Ther. Targets, 2013, 17(11), 1303-1328.
[19]
Bournazou, E.; Bromberg, J. Targeting the tumor microenvironment: JAK-STAT3 signaling. JAK-STAT, 2013, 2(2), e23828.
[20]
Heo, T.H.; Wahler, J.; Suh, N. Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer. Oncotarget, 2016, 7(13), 15460-15473.
[21]
Bharti, R.; Dey, G.; Banerjee, I.; Dey, K.K.; Parida, S.; Kumar, B.P.; Das, C.K.; Pal, I.; Mukherjee, M.; Misra, M. Somatostatin receptor targeted liposomes with Diacerein inhibit IL-6 for breast cancer therapy. Cancer Lett., 2017, 388, 292-302.
[22]
Lee, B-R.; Kwon, B-E.; Hong, E-H.; Shim, A.; Song, J-H.; Kim, H-M.; Chang, S-Y.; Kim, Y-J.; Kweon, M-N.; Youn, J-I. Interleukin-10 attenuates tumour growth by inhibiting interleukin-6/signal transducer and activator of transcription 3 signalling in myeloid-derived suppressor cells. Cancer Lett., 2016, 381(1), 156-164.
[23]
Tanaka, T.; Narazaki, M.; Kishimoto, T. Therapeutic targeting of the interleukin-6 receptor. Annu. Rev. Pharmacol. Toxicol., 2012, 52, 199-219.
[24]
Holmer, R.; Goumas, F.A.; Waetzig, G.H.; Rose-John, S.; Kalthoff, H. Interleukin-6: a villain in the drama of pancreatic cancer development and progression. Hepatobiliary Pancreat. Dis. Int., 2014, 13(4), 371-380.
[25]
Denley, S.M.; Jamieson, N.B.; McCall, P.; Oien, K.A.; Morton, J.P.; Carter, C.R.; Edwards, J.; McKay, C.J. Activation of the IL-6R/Jak/stat pathway is associated with a poor outcome in resected pancreatic ductal adenocarcinoma. J. Gastrointest. Surg., 2013, 17(5), 887-898.
[26]
Lesina, M.; Kurkowski, M.U.; Ludes, K.; Rose-John, S.; Treiber, M.; Klöppel, G.; Yoshimura, A.; Reindl, W.; Sipos, B.; Akira, S. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell, 2011, 19(4), 456-469.
[27]
Goumas, F.A.; Holmer, R.; Egberts, J.H.; Gontarewicz, A.; Heneweer, C.; Geisen, U.; Hauser, C.; Mende, M.M.; Legler, K.; Röcken, C. Inhibition of IL‐6 signaling significantly reduces primary tumor growth and recurrencies in orthotopic xenograft models of pancreatic cancer. Int. J. Cancer, 2015, 137(5), 1035-1046.
[28]
Li, H.; Xiao, H.; Lin, L.; Jou, D.; Kumari, V.; Lin, J.; Li, C. Drug design targeting protein–protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning: Discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 interface. J. Med. Chem., 2014, 57(3), 632-641.
[29]
Wu, X.; Cao, Y.; Xiao, H.; Li, C.; Lin, J. Bazedoxifene as a novel GP130 inhibitor for pancreatic cancer therapy. Mol. Cancer Ther., 2016, 15(11), 2609-2619.
[30]
Pop, V-V.; Seicean, A.; Lupan, I.; Samasca, G.; Burz, C-C. IL-6 roles-Molecular pathway and clinical implication in pancreatic cancer-A systemic review. Immunol. Lett., 2016, 181, 45-50.
[31]
Miura, T.; Mitsunaga, S.; Ikeda, M.; Shimizu, S.; Ohno, I.; Takahashi, H.; Furuse, J.; Inagaki, M.; Higashi, S.; Kato, H. Characterization of patients with advanced pancreatic cancer and high serum interleukin-6 levels. Pancreas, 2015, 44(5), 756-763.
[32]
Yadav, A.; Kumar, B.; Teknos, T.N.; Kumar, P. Bazedoxifene enhances the anti-tumor effects of cisplatin and radiation treatment by blocking IL-6 signaling in head and neck cancer. Oncotarget, 2016, 8(40), 66912-66924.
[33]
Racker, E. Bioenergetics and the problem of tumor growth: an understanding of the mechanism of the generation and control of biological energy may shed light on the problem of tumor growth. Am. Sci., 1972, 60(1), 56-63.
[34]
Koppenol, W.H.; Bounds, P.L.; Dang, C.V. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat. Rev. Cancer, 2011, 11(5), 325-337.
[35]
Ghavami, S.; Hashemi, M.; Ande, S.R.; Yeganeh, B.; Xiao, W.; Eshraghi, M.; Bus, C.J.; Kadkhoda, K.; Wiechec, E.; Halayko, A.J. Apoptosis and cancer: Mutations within caspase genes. J. Med. Genet., 2009, 46(8), 497-510.
[36]
McIlwain, D.R.; Berger, T.; Mak, T.W. Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol., 2013, 5(4), a008656.
[37]
Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin., 2013, 63(1), 11-30.
[38]
Moore, M.J.; Goldstein, D.; Hamm, J.; Figer, A.; Hecht, J.R.; Gallinger, S.; Au, H.J.; Murawa, P.; Walde, D.; Wolff, R.A. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol., 2007, 25(15), 1960-1966.
[39]
Scheller, J.; Chalaris, A.; Schmidt-Arras, D.; Rose-John, S. The pro-and anti-inflammatory properties of the cytokine interleukin-6. BBA-Mol. Cell Res., 2011, 1813(5), 878-888.
[40]
Calabrese, L.H.; Rose-John, S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat. Rev. Rheumatol., 2014, 10(12), 720-727.
[41]
Tenhumberg, S.; Waetzig, G.H.; Chalaris, A.; Rabe, B.; Seegert, D.; Scheller, J.; Rose-John, S.; Grötzinger, J. Structure-guided optimization of the interleukin-6 trans-signaling antagonist sgp130. J. Biol. Chem., 2008, 283(40), 27200-27207.
[42]
Chines, A.A.; Komm, B.S. Bazedoxifene acetate: A novel selective estrogen receptor modulator for the prevention and treatment of postmenopausal osteoporosis. Drugs Today (Barc), 2009, 45(7), 507-520.
[43]
Komm, B.S.; Kharode, Y.P.; Bodine, P.V.; Harris, H.A.; Miller, C.P.; Lyttle, C.R. Bazedoxifene acetate: A selective estrogen receptor modulator with improved selectivity. Endocrinology, 2005, 146(9), 3999-4008.
[44]
Archer, D.F.; Pinkerton, J.V.; Utian, W.H.; Menegoci, J.C.; de Villiers, T.J.; Yuen, C.K.; Levine, A.B.; Chines, A.A.; Constantine, G.D. Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause, 2009, 16(6), 1109-1115.
[45]
Palacios, S.; de Villiers, T.J.; Nardone, F.D.C.; Levine, A.B.; Williams, R.; Hines, T.; Mirkin, S.; Chines, A.A.; Group, B.S. Assessment of the safety of long-term bazedoxifene treatment on the reproductive tract in postmenopausal women with osteoporosis: Results of a 7-year, randomized, placebo-controlled, phase 3 study. Maturitas, 2013, 76(1), 81-87.
[46]
Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science, 2009, 324(5930), 1029-1033.
[47]
Cron, L.; Allen, T.; Febbraio, M.A. The role of gp130 receptor cytokines in the regulation of metabolic homeostasis. J. Exp. Biol., 2016, 219(2), 259-265.
[48]
Carey, A.L.; Steinberg, G.R.; Macaulay, S.L.; Thomas, W.G.; Holmes, A.G.; Ramm, G.; Prelovsek, O.; Hohnen-Behrens, C.; Watt, M.J.; James, D.E. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes, 2006, 55(10), 2688-2697.
[49]
Ando, M.; Uehara, I.; Kogure, K.; Asano, Y.; Nakajima, W.; Abe, Y.; Kawauchi, K.; Tanaka, N. Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3. J. Nippon Med. Sch., 2010, 77(2), 97-105.
[50]
Han, J.; Meng, Q.; Xi, Q.; Zhang, Y.; Zhuang, Q.; Han, Y.; Jiang, Y.; Ding, Q.; Wu, G. Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer. Int. J. Oncol., 2016, 48(1), 215-224.
[51]
Hirschhaeuser, F.; Sattler, U.G.; Mueller-Klieser, W. Lactate: A metabolic key player in cancer. Cancer Res., 2011, 71(22), 6921-6925.

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