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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

The Opposite Effect of L-kynurenine and Ahr Inhibitor Ch223191 on Apoptotic Protein Expression in Pancreatic Carcinoma Cells (Panc-1)

Author(s): Anna Leja-Szpak*, Marta Góralska, Paweł Link-Lenczowski, Urszula Czech, Katarzyna Nawrot-Porąbka, Joanna Bonior and Jolanta Jaworek

Volume 19, Issue 17, 2019

Page: [2079 - 2090] Pages: 12

DOI: 10.2174/1871520619666190415165212

Price: $65


Background: L-kynurenine, derivate of L-tryptophan, is synthetized by indoleamine 2,3-dioxygenase (IDO). The effects of L-kynurenine depend on its binding to an aryl hydrocarbon receptor (AhR).

Objective: The aim of this study was to investigate the changes within the apoptotic pathway in PANC-1 cells subjected to L-kynurenine or L-tryptophan considering the production of anti-apoptotic proteins from the IAPs and Bcl-2 family, as well as the regulation of NF-κB signaling.

Methods: The investigated substances were added alone or in combination with the AhR inhibitor (CH223191) to cultures of PANC-1 cells. Cytoplasmic and nuclear proteins were analyzed by immunoblotting and cells were incubated with the investigated substances to determine cytotoxicity and proliferative effects.

Results: Incubation of PANC-1 cells with L-kynurenine or L-tryptophan resulted in the increase in antiapoptotic cIAP-1, cIAP-2, XIAP and Bcl-2 expression and a decrease in pro-apoptotic Bax. These changes were accompanied by the reduction of active caspases -9, -3 and PARP-1. The treatment leads to translocation and enhanced production of nuclear NF-κB p50 and Bcl-3. Incubation of the cells with AhR blocker either alone or together with L-kynurenine or L-tryptophan resulted in the opposite effect, leading to the downregulation of IAPs and Bcl-2, upregulation of Bax and caspases expression.

Conclusion: 1) L-kynurenine and its precursor promote anti-apoptotic effects through the modulation of IDOdependent pathway and regulation of IAPs, Bcl-2 and NF-κB family members in pancreatic carcinoma cells 2) inhibition of AhR by CH223191 exerts an apoptosis-promoting effect, and this observation might suggest the potential use of this compound in pancreatic cancer therapy.

Keywords: L-kynurenine, L-tryptophan, IDO, AhR, pancreatic human carcinoma cells - PANC-1, apoptosis, caspases expression.

Graphical Abstract
Chen, Y.; Guillemin, G.J. Kynurenine pathway metabolites in humans: Disease and healthy states. Int. J. Tryptophan Res., 2009, 2, 1-19.
Munn, D.H.; Mellor, A.L. IDO in the tumor microenvironment: Inflammation, counter-regulation, and tolerance. Trends Immunol., 2016, 37(3), 193-207.
Cavia-Saiz, M.; Muñiz, P.; De Santiago, R.; Herreros-Villanueva, M.; Garcia-Giron, C.; Lopez, A.S.; Coma-Del Corral, M.J. Changes in the levels of thioredoxin and indoleamine-2,3-dioxygenase activity in plasma of patients with colorectal cancer treated with chemotherapy. Biochem. Cell Biol., 2012, 90(2), 173-178.
Wei, L.; Zhu, S.; Li, M.; Li, F.; Wei, F.; Liu, J.; Ren, X. High indoleamine 2,3-dioxygenase is corelated with microvessel density and worse prognosis in breast cancer. Front. Immunol., 2018, 17(9), 724.
Wang, Y.; Hu, G.F.; Wang, Z.H. The status of immunosuppression in patients with stage IIIB or IV non-small-cell lung cancer correlates with the clinical characteristics and response to chemotherapy. OncoTargets Ther., 2017, 19(10), 3557-3566.
Moffett, J.R.; Namboodiri, M.A. Tryptophan and the immune response. Immunol. Cell Biol., 2003, 81(4), 247-265.
Tsuji, N.; Fukuda, K.; Nagata, Y.; Okada, H.; Haga, A.; Hatakeyama, S.; Yoshida, S.; Okamoto, T.; Hosaka, M.; Sekine, K.; Ohtaka, K.; Yamamoto, S.; Otaka, M.; Grave, E.; Itoh, H. The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90. FEBS Open Bio, 2014, 16(4), 796-803.
Quintana, F.J.; Murugaiyan, G.; Farez, M.F.; Mitsdoerffer, M.; Tukpah, A.M.; Burns, E.J.; Weiner, H.L. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA, 2010, 107, 20768-20773.
Wang, S.; El-Deiry, W.S. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene, 2003, 22, 8628-8633.
Du, C.; Fang, M.; Li, Y.; Li, L.; Wang, X. Smac, a mitochondrial protein that promotes cytochrome C-dependent caspase activation by eliminating IAP inhibition. Cell, 2000, 102(1), 33-42.
Peixoto, P.M.; Lue, J.K.; Ryu, S.Y.; Wroble, B.N.; Sible, J.C.; Kinnally, K.W. Mitochondrial apoptosis-induced channel (MAC) function triggers a Bax/Bak-dependent bystander effect. Am. J. Pathol., 2011, 178(1), 48-54.
Saldeen, J.; Tillmar, L.; Karlsson, E.; Welsh, N. Nicotinamide- and caspase-mediated inhibition of poly(ADP-ribose) polymerase are associated with p53-independent cell cycle (G2) arrest and apoptosis. Mol. Cell. Biochem., 2003, 243(1-2), 113-122.
Kocab, A.J.; Duckett, C.S. Inhibitor of apoptosis proteins as intra-cellular signaling intermediates. FEBS J., 2016, 283(2), 221-231.
Wu, J.; Liu, T.; Rios, Z.; Mei, Q.; Lin, X.; Cao, S. Heat shock proteins and cancer. Trends Pharmacol. Sci., 2017, 38(3), 226-256.
Berkovich, L.; Earon, G.; Ron, I.; Rimmon, A.; Vexler, A.; Lev-Ari, S. Moringa oleifera aqueous leaf extract down-regulates nuclear factor-kappaB and increases cytotoxic effect of chemotherapy in pancreatic cancer cells. BMC Complement. Altern. Med., 2013, 19(13), 212.
Garg, B.; Giri, B.; Modi, S.; Sethi, V.; Castro, I.; Umland, O.; Ban, Y.; Lavania, S.; Dawra, R.; Banerjee, S.; Vickers, S.; Merchant, N.B.; Chen, S.X.; Gilboa, E.; Ramakrishnan, S.; Saluja, A.; Dudeja, V. NFκB in pancreatic stellate cells reduces infiltration of tumors by cytotoxic T cells and killing of cancer cells, via upregulation of CXCL12. Gastroenterology, 2018, S0016-5085(18), 34656.
Forman, K.; Vara, E.; García, C.; Kireev, R.; Cuesta, S.; Acuña-Castroviejo, D.; Tresguerres, J.A. Influence of aging and growth hormone on different members of the NFkB family and IkB expression in the heart from a murine model of senescence-accelerated aging. Exp. Gerontol., 2016, 73, 114-120.
Horie, K.; Ma, J.; Umezawa, K. Inhibition of canonical NF-κB nuclear localization by (-)-DHMEQ via impairment of DNA binding. Oncol. Res., 2015, 22(2), 105-115.
Gehrke, N.; Wörns, M.A.; Mann, A.; Huber, Y.; Hoevelmeyer, N.; Longerich, T.; Waisman, A.; Galle, P.R.; Schattenberg, J.M. Hepatic B cell leukemia-3 suppresses chemically-induced hepatocarcinogenesis in mice through altered MAPK and NF-κB activation. Oncotarget, 2016, 8(34), 56095-56109.
Leja-Szpak, A.; Pierzchalski, P.; Goralska, M.; Jastrzębska, M.; Link-Lenczowski, P.; Bonior, J.; Pierzchalski, P.; Jaworek, J. Kynuramines induce overexpression of heat shock proteins in pancreatic cancer cells via 5-hydroxytryptamine and MT1/MT2 receptors. J. Physiol. Pharmacol., 2015, 66(5), 711-718.
Hyun, J.J.; Lee, H.S.; Keum, B.; Seo, Y.S.; Jeen, Y.T.; Chun, H.J.; Um, S.H.; Kim, C.D. Expression of heat shock protein 70 modulates the chemoresponsiveness of pancreatic cancer. Gut Liver, 2013, 7(6), 739-746.
Owen, S.; Zhao, H.; Dart, A.; Wang, Y.; Ruge, F.; Gao, Y.; Wei, C.; Wu, Y.; Jiang, W.G. Heat shock protein 27 is a potential indicator for response to Yang Zheng Xiao Ji and chemotherapy agents in cancer cells. Int. J. Oncol., 2016, 49(5), 1839-1847.
Belalcazar, A.; Shaib, W.L.; Farren, M.R.; Zhang, C.; Chen, Z.; Yang, L.; Lesinski, G.B.; El-Rayes, B.F.; Nagaraju, G.P. Inhibiting heat shock protein 90 and the ubiquitin-proteasome pathway impairs metabolic homeostasis and leads to cell death in human pancreatic cancer cells. Cancer, 2017, 123(24), 4924-4933.
Jia, Y.; Wang, H.; Wang, Y.; Wang, T.; Wang, M.; Ma, M.; Duan, Y.; Meng, X.; Liu, L. Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients. Int. J. Cancer, 2015, 137(5), 1095-1106.
Lucarelli, G.; Rutigliano, M.; Ferro, M.; Giglio, A.; Intini, A.; Triggiano, F.; Palazzo, S.; Gigante, M.; Castellano, G.; Ranieri, E.; Buonerba, C.; Terracciano, D.; Sanguedolce, F.; Napoli, A.; Maiorano, E.; Morelli, F.; Ditonno, P.; Battaglia, M. Activation of the kynurenine pathway predicts poor outcome in patients with clear cell renal cell carcinoma. Urol. Oncol., 2017, 35(7), 461.e15-461.e27.
Ye, J.; Liu, H.; Hu, Y.; Li, P.; Zhang, G.; Li, Y. Tumoral indoleamine 2,3-dioxygenase expression predicts poor outcome in laryngeal squamous cell carcinoma. Virchows Arch., 2013, 462(1), 73-81.
Calleja, P.; Irache, J.M.; Zandueta, C.; Martínez-Oharriz, C.; Espuelas, S. A combination of nanosystems for the delivery of cancer chemoimmunotherapeutic combinations: 1-Methyltryptophan nanocrystals and paclitaxel nanoparticles. Pharmacol. Res., 2017, 126, 77-83.
Zhang, T.; Tan, X.L.; Xu, Y.; Wang, Z.Z.; Xiao, C.H.; Liu, R. Expression and prognostic value of indoleamine 2,3-dioxygenase in pancreatic cancer. Chin. Med. J. (Engl.), 2017, 130(6), 710-716.
Koblish, H.K.; Hansbury, M.J.; Bowman, K.J.; Yang, G.; Neilan, C.L.; Haley, P.J.; Burn, T.C.; Waeltz, P.; Sparks, R.B.; Yue, E.W.; Combs, A.P.; Scherle, P.A.; Vaddi, K.; Fridman, J.S. Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol. Cancer Ther., 2010, 9(2), 489-498.
Chung, T.W.; Tan, K.T.; Chan, H.L.; Lai, M.D.; Yen, M.C.; Li, Y.R.; Lin, S.H.; Lin, C.C. Induction of indoleamine 2,3-dioxygenase (IDO) enzymatic activity contributes to interferon-gamma induced apoptosis and death receptor 5 expression in human non-small cell lung cancer cells. Asian Pac. J. Cancer Prev., 2014, 15(18), 7995-8001.
Chuang, S.C.; Fanidi, A.; Ueland, P.M.; Relton, C.; Midttun, O.; Vollset, S.E.; Gunter, M.J.; Seckl, M.J.; Travis, R.C.; Wareham, N.; Trichopoulou, A.; Lagiou, P.; Trichopoulos, D.; Peeters, P.H.; Bueno-de-Mesquita, H.B.; Boeing, H.; Wientzek, A.; Kuehn, T.; Kaaks, R.; Tumino, R.; Agnoli, C.; Palli, D.; Naccarati, A.; Aicua, E.A.; Sánchez, M.J.; Quirós, J.R.; Chirlaque, M.D.; Agudo, A.; Johansson, M.; Grankvist, K.; Boutron-Ruault, M.C.; Clavel-Chapelon, F.; Fagherazzi, G.; Weiderpass, E.; Riboli, E.; Brennan, P.J.; Vineis, P.; Johansson, M. Circulating biomarkers of tryptophan and the kynurenine pathway and lung cancer risk. Cancer Epidemiol. Biomarkers Prev., 2014, 23(3), 461-468.
Qi, Y.; Wang, R.; Zhao, L.; Lv, L.; Zhou, F.; Zhang, T.; Lu, F.; Yan, H.; Duan, G. Celastrol suppresses tryptophan catabolism in human colon cancer cells as revealed by metabolic profiling and targeted metabolite analysis. Biol. Pharm. Bull., 2018, 41(8), 1243-1250.
Dharane Neé Ligam, P.; Manuelpillai, U.; Wallace, E.; Walker, D.W. NFκB-dependent increase of kynurenine pathway activity in human placenta: Inhibition by sulfasalazine. Placenta, 2010, 31(11), 997-1002.
D’Amato, N.C.; Rogers, T.J.; Gordon, M.A.; Greene, L.I.; Cochrane, D.R.; Spoelstra, N.S.; Nemkov, T.G.; D’Alessandro, A.; Hansen, K.C.; Richer, J.K.A. TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. Cancer Res., 2015, 75(21), 4651-4664.
Chandler, N.M.; Canete, J.J.; Callery, M.P. Increased expression of NF-kappa B subunits in human pancreatic cancer cells. J. Surg. Res., 2004, 118(1), 9-14.
Li, Q.; Yang, G.; Feng, M.; Zheng, S.; Cao, Z.; Qiu, J.; You, L.; Zheng, L.; Hu, Y.; Zhang, T.; Zhao, Y. NF-κB in pancreatic cancer: Its key role in chemoresistance. Cancer Lett., 2018, 421, 127-134.
Yu, C.; Chen, S.; Guo, Y.; Sun, C. Oncogenic TRIM31 confers gemcitabine resistance in pancreatic cancer via activating the NF-κB signaling pathway. Theranostics, 2018, 8(12), 3224-3236.
Thornburg, N.J.; Pathmanathan, R.; Raab-Traub, N. Activation of nuclear factor-kappaB p50 homodimer/Bcl-3 complexes in nasopharyngeal carcinoma. Cancer Res., 2003, 63(23), 8293-82301.
Puvvada, S.D.; Funkhouser, W.K.; Greene, K.; Deal, A.; Chu, H.; Baldwin, A.S.; Tepper, J.E.; O’Neil, B.H. NF-kB and Bcl-3 activation are prognostic in metastatic colorectal cancer. Oncology, 2010, 78(3-4), 181-188.
Tu, K.; Liu, Z.; Yao, B.; Xue, Y.; Xu, M.; Dou, C.; Yin, G.; Wang, J. BCL-3 promotes the tumor growth of hepatocellular carcinoma by regulating cell proliferation and the cell cycle through cyclin D1. Oncol. Rep., 2016, 35(4), 2382-2390.
Viatour, P.; Bentires-Alj, M.; Chariot, A.; Deregowski, V.; de Leval, L.; Merville, M.P.; Bours, V. NF- kappa B2/p100 induces Bcl-2 expression. Leukemia, 2003, 17(7), 1349-1356.
Vogel, C.F.; Goth, S.R.; Dong, B.; Pessah, I.N.; Matsumura, F. Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase. Biochem. Biophys. Res. Commun., 2008, 375(3), 331-335.
Litzenburger, U.M.; Opitz, C.A.; Sahm, F.; Rauschenbach, K.J.; Trump, S.; Winter, M.; Ott, M.; Ochs, K.; Lutz, C.; Liu, X.; Anastasov, N.; Lehmann, I.; Höfer, T.; von Deimling, A.; Wick, W.; Platten, M. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AhR. Oncotarget, 2014, 5(4), 1038-1051.
Zhao, B.; Degroot, D.E.; Hayashi, A.; He, G.; Denison, M.S. CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor. Toxicol. Sci., 2010, 117(2), 393-403.
Moyer, B.J.; Rojas, I.Y.; Kerley-Hamilton, J.S.; Hazlett, H.F.; Nemani, K.V.; Trask, H.W.; West, R.J.; Lupien, L.E.; Collins, A.J.; Ringelberg, C.S.; Gimi, B.; Kinlaw, W.B., 3rd; Tomlinson, C.R. Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AhR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1. Toxicol. Appl. Pharmacol., 2016, 300, 13-24.
Choi, E.Y.; Lee, H.; Dingle, R.W.; Kim, K.B.; Swanson, H.I. Development of novel CH223191-based antagonists of the aryl hydrocarbon receptor. Mol. Pharmacol., 2012, 81(1), 3-11.
Stanford, E.A.; Wang, Z.; Novikov, O.; Mulas, F.; Landesman-Bollag, E.; Monti, S.; Smith, B.W.; Seldin, D.C.; Murphy, G.J.; Sherr, D.H. The role of the aryl hydrocarbon receptor in the development of cells with the molecular and functional characteristics of cancer stem-like cells. BMC Biol., 2016, 16(14), 20.
Yin, J.; Sheng, B.; Han, B.; Pu, A.; Yang, K.; Li, P.; Wang, Q.; Xiao, W.; Yang, H. The AhR is involved in the regulation of LoVo cell proliferation through cell cycle-associated proteins. Cell Biol. Int., 2016, 40(5), 560-568.
Zhang, X.; Paun, A.; Claudio, E.; Wang, H.; Siebenlist, U. The tumor promoter and NF-κB modulator Bcl-3 regulates splenic B cell development. J. Immunol., 2013, 191(12), 5984-5992.
Tassi, I.; Rikhi, N.; Claudio, E.; Wang, H.; Tang, W.; Ha, H.L.; Saret, S.; Kaplan, D.H.; Siebenlist, U. The NF-κB regulator Bcl-3 modulates inflammation during contact hypersensitivity reactions in radioresistant cells. Eur. J. Immunol., 2015, 45(4), 1059-1068.

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