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Anti-Cancer Agents in Medicinal Chemistry

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

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Research Article

Periplogenin Activates ROS-ER Stress Pathway to Trigger Apoptosis via BIP-eIF2α- CHOP and IRE1α-ASK1-JNK Signaling Routes

Author(s): Yingjuan Yang, Yana Liu, Yanhua Zhang, Wei Ji, Lan Wang and Shao C. Lee*

Volume 21, Issue 1, 2021

Published on: 08 July, 2020

Page: [61 - 70] Pages: 10

DOI: 10.2174/1871520620666200708104559

Price: $65

Abstract

Background: Periplogenin (PPG), a natural compound isolated from traditional Chinese herb Cortex Periplocae, has been reported to possess anti-inflammatory and anti-cancer properties.

Objective: The present study aims to investigate the antitumor effects of PPG and the underlying mechanism in human colorectal cancer cells.

Methods: The inhibition of cell growth in vitro was assessed by MTT assay. The induction of apoptosis and the ROS production induced by PPG was investigated by flow cytometry analysis. Western blotting was applied to measure the protein expression. Small interference RNA (siRNA) and a specific pharmacological inhibitor were used to knock down or inhibit the expression of related genes.

Results: PPG was able to cause the production of ROS, inhibit the cancer cell growth and induce apoptosis. Nacetylcysteine was able to inhibit ROS production and apoptosis. PPG up-regulated the protein levels of BIP, peIF2α and CHOP as well as IRE1α and p-JNK, and down-regulated the protein level of p-ASK1, all of which were reversed by N-acetylcysteine. Importantly, knockdown of CHOP or JNK protein level attenuated the PPGelicited apoptosis.

Conclusion: PPG-induced apoptosis was regulated by ROS-mediated BIP/eIF2α/CHOP and BIP/ASK1/JNK signaling pathways in colon cancer cells, suggesting that PPG is a promising therapeutic agent for the treatment of human colon cancer.

Keywords: Periplogenin, ROS, ER stress, apoptosis, colon cancer cells, MTT assay.

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[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2017. CA Cancer J. Clin., 2017, 67(1), 7-30.
[http://dx.doi.org/10.3322/caac.21387 ] [PMID: 28055103]
[2]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492 ] [PMID: 30207593]
[3]
Radogna, F.; Dicato, M.; Diederich, M. Cancer-type-specific crosstalk between autophagy, necroptosis and apoptosis as a pharmacological target. Biochem. Pharmacol., 2015, 94(1), 1-11.
[http://dx.doi.org/10.1016/j.bcp.2014.12.018 ] [PMID: 25562745]
[4]
Wang, P.; Yang, H.L.; Yang, Y.J.; Wang, L.; Lee, S.C. Overcome cancer cell drug resistance using natural products. Evid. Based Complement. Alternat. Med., 2015, 2015767136
[http://dx.doi.org/10.1155/2015/767136] [PMID: 26421052]
[5]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod., 2016, 79(3), 629-661.
[http://dx.doi.org/10.1021/acs.jnatprod.5b01055 ] [PMID: 26852623]
[6]
Zhang, Y.W.; Bao, Y.L.; Wu, Y.; Yu, C.L.; Li, Y.X. 17βH-Periplogenin, a cardiac aglycone from the root bark of Periploca sepium Bunge. Acta Crystallogr. Sect. E Struct. Rep. Online, 2012, 68(Pt 6), o1582-o1583.
[http://dx.doi.org/10.1107/S1600536812018521 ] [PMID: 22719394]
[7]
Panda, S.; Kar, A. Periplogenin, isolated from Lagenaria siceraria, ameliorates L-T4-induced hyperthyroidism and associated cardiovascular problems. Horm. Metab. Res., 2011, 43(3), 188-193.
[http://dx.doi.org/10.1055/s-0031-1271621 ] [PMID: 21287437]
[8]
Li, L.; Zhao, L.M.; Dai, S.L.; Cui, W.X.; Lv, H.L.; Chen, L.; Shan, B.E. Periplocin extracted from cortex periplocae induced apoptosis of gastric cancer cells via the ERK1/2-EGR1 pathway. Cell. Physiol. Biochem., 2016, 38(5), 1939-1951.
[http://dx.doi.org/10.1159/000445555 ] [PMID: 27160973]
[9]
Lohberger, B.; Wagner, S.; Wohlmuther, J.; Kaltenegger, H.; Stuendl, N.; Leithner, A.; Rinner, B.; Kunert, O.; Bauer, R.; Kretschmer, N. Periplocin, the most anti-proliferative constituent of Periploca sepium, specifically kills liposarcoma cells by death receptor mediated apoptosis. Phytomedicine, 2018, 51, 162-170.
[http://dx.doi.org/10.1016/j.phymed.2018.10.008 ] [PMID: 30466613]
[10]
Lu, Z.; Song, Q.; Yang, J.; Zhao, X.; Zhang, X.; Yang, P.; Kang, J. Comparative proteomic analysis of anti-cancer mechanism by periplocin treatment in lung cancer cells. Cell. Physiol. Biochem., 2014, 33(3), 859-868.
[http://dx.doi.org/10.1159/000358658 ] [PMID: 24685647]
[11]
Lu, Z.J.; Zhou, Y.; Song, Q.; Qin, Z.; Zhang, H.; Zhou, Y.J.; Gou, L.T.; Yang, J.L.; Luo, F. Periplocin inhibits growth of lung cancer in vitro and in vivo by blocking AKT/ERK signaling pathways. Cell. Physiol. Biochem., 2010, 26(4-5), 609-618.
[http://dx.doi.org/10.1159/000322328 ] [PMID: 21063098]
[12]
Zhao, L.; Shan, B.; Du, Y.; Wang, M.; Liu, L.; Ren, F.Z. Periplocin from Cortex periplocae inhibits cell growth and down-regulates survivin and c-myc expression in colon cancer in vitro and in vivo via beta-catenin/TCF signaling. Oncol. Rep., 2010, 24(2), 375-383.
[PMID: 20596624]
[13]
Ojha, R.; Amaravadi, R.K. Targeting the unfolded protein response in cancer. Pharmacol. Res., 2017, 120, 258-266.
[http://dx.doi.org/10.1016/j.phrs.2017.04.003 ] [PMID: 28396092]
[14]
Sisinni, L.; Pietrafesa, M.; Lepore, S.; Maddalena, F.; Condelli, V.; Esposito, F.; Landriscina, M. Endoplasmic reticulum stress and unfolded protein response in breast cancer: The balance between apoptosis and autophagy and its role in drug resistance. Int. J. Mol. Sci., 2019, 20(4)E857
[http://dx.doi.org/10.3390/ijms20040857] [PMID: 30781465]
[15]
Oakes, S.A. Endoplasmic reticulum proteostasis: A key checkpoint in cancer., Am. J. Physiol. Cell Ph., 2016, 312(2), ajpcell. 00266.2016.
[16]
Wang, M.; Kaufman, R.J. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat. Rev. Cancer, 2014, 14(9), 581-597.
[http://dx.doi.org/10.1038/nrc3800 ] [PMID: 25145482]
[17]
Wang, M.; Law, M.E.; Castellano, R.K.; Law, B.K. The unfolded protein response as a target for anticancer therapeutics. Crit. Rev. Oncol. Hematol., 2018, 127, 66-79.
[http://dx.doi.org/10.1016/j.critrevonc.2018.05.003 ] [PMID: 29891114]
[18]
Zhu, Y.N.; Zhao, W.M.; Yang, Y.F.; Liu, Q.F.; Zhou, Y.; Tian, J.; Ni, J.; Fu, Y.F.; Zhong, X.G.; Tang, W.; Zhou, R.; He, P.L.; Li, X.Y.; Zuo, J.P. Periplocoside E, an effective compound from Periploca sepium Bge, inhibited T cell activation in vitro and in vivo. J. Pharmacol. Exp. Ther., 2006, 316(2), 662-669.
[http://dx.doi.org/10.1124/jpet.105.093732 ] [PMID: 16204471]
[19]
Yuan, X.; Yu, B.; Wang, Y.; Jiang, J.; Liu, L.; Zhao, H.; Qi, W.; Zheng, Q. Involvement of endoplasmic reticulum stress in isoliquiritigenin-induced SKOV-3 cell apoptosis. Recent Pat Anticancer Drug Discov., 2013, 8(2), 191-199.
[http://dx.doi.org/10.2174/1574892811308020007 ] [PMID: 22963151]
[20]
Zhang, W.J.; Song, Z.B.; Bao, Y.L.; Li, W.L.; Yang, X.G.; Wang, Q.; Yu, C.L.; Sun, L.G.; Huang, Y.X.; Li, Y.X. Periplogenin induces necroptotic cell death through oxidative stress in HaCaT cells and ameliorates skin lesions in the TPA- and IMQ-induced psoriasis-like mouse models. Biochem. Pharmacol., 2016, 105, 66-79.
[http://dx.doi.org/10.1016/j.bcp.2016.02.001 ] [PMID: 26850986]
[21]
Lam, K.S. New aspects of natural products in drug discovery. Trends Microbiol., 2007, 15(6), 279-289.
[http://dx.doi.org/10.1016/j.tim.2007.04.001 ] [PMID: 17433686]
[22]
Li, Y.; Liu, Y.B.; Yu, S.S.; Chen, X.G.; Wu, X.F.; Ma, S.G.; Qu, J.; Hu, Y.C.; Liu, J.; Lv, H.N. Cytotoxic cardenolides from the stems of periploca forrestii.Steroids,, 2012, 77(5), 0-381.
[23]
Finkel, T. Signal transduction by mitochondrial oxidants. J. Biol. Chem., 2012, 287(7), 4434-4440.
[http://dx.doi.org/10.1074/jbc.R111.271999 ] [PMID: 21832045]
[24]
Handy, D.E.; Loscalzo, J. Redox regulation of mitochondrial function. Antioxid. Redox Signal., 2012, 16(11), 1323-1367.
[http://dx.doi.org/10.1089/ars.2011.4123]
[25]
Malhotra, J.D.; Kaufman, R.J. Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double-edged sword? Antioxid. Redox Signal., 2007, 9(12), 2277-2293.
[http://dx.doi.org/10.1089/ars.2007.1782]
[26]
Schrader, M.; Fahimi, H.D. Peroxisomes and oxidative stress. Biochim. Biophys. Acta, 2006, 1763(12), 1755-1766.
[http://dx.doi.org/10.1016/j.bbamcr.2006.09.006 ] [PMID: 17034877]
[27]
Kumar, A.; Singh, B.; Mahajan, G.; Sharma, P.R.; Bharate, S.B.; Mintoo, M.J.; Mondhe, D.M. A novel colchicine-based microtubule inhibitor exhibits potent antitumor activity by inducing mitochondrial mediated apoptosis in MIA PaCa-2 pancreatic cancer cells. Tumour Biol., 2016, 37(10), 13121-13136.
[http://dx.doi.org/10.1007/s13277-016-5160-5 ] [PMID: 27449046]
[28]
Park, S.; Lim, W.; Bazer, F.W.; Song, G. Apigenin induces ROS-dependent apoptosis and ER stress in human endometriosis cells., 2018, 233(4), 3055-3065.
[http://dx.doi.org/10.1002/jcp.26054 ]
[29]
Kuo, P.L.; Chen, C.Y.; Hsu, Y.L. Isoobtusilactone A induces cell cycle arrest and apoptosis through reactive oxygen species/apoptosis signal-regulating kinase 1 signaling pathway in human breast cancer cells. Cancer Res., 2007, 67(15), 7406-7420.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-1089 ] [PMID: 17671211]
[30]
Yang, Y.; Zhang, Y.; Wang, L.; Lee, S. Levistolide A induces apoptosis via ROS-mediated ER stress pathway in colon cancer cells. Cell. Physiol. Biochem., 2017, 42(3), 929-938.
[http://dx.doi.org/10.1159/000478647 ] [PMID: 28662507]
[31]
Holmström, K.M.; Finkel, T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat. Rev. Mol. Cell Biol., 2014, 15(6), 411-421.
[http://dx.doi.org/10.1038/nrm3801 ] [PMID: 24854789]
[32]
Senft, D.; Ronai, Z.A. UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem. Sci., 2015, 40(3), 141-148.
[http://dx.doi.org/10.1016/j.tibs.2015.01.002 ] [PMID: 25656104]
[33]
Di, S.; Fan, C.; Ma, Z.; Li, M.; Guo, K.; Han, D.; Li, X.; Mu, D.; Yan, X. PERK/eIF-2α/CHOP Pathway Dependent ROS Generation Mediates Butein-induced Non-small-cell Lung Cancer Apoptosis and G2/M Phase Arrest. Int. J. Biol. Sci., 2019, 15(8), 1637-1653.
[http://dx.doi.org/10.7150/ijbs.33790 ] [PMID: 31360107]
[34]
Kim, H.R.; Lee, G.H.; Cho, E.Y.; Chae, S.W.; Ahn, T.; Chae, H.J. Bax inhibitor 1 regulates ER-stress-induced ROS accumulation through the regulation of cytochrome P450 2E1. J. Cell Sci., 2009, 122(Pt 8), 1126-1133.
[http://dx.doi.org/10.1242/jcs.038430 ] [PMID: 19339548]
[35]
Liu, Y.H.; Weng, Y.P.; Lin, H.Y.; Tang, S.W.; Chen, C.J.; Liang, C.J.; Ku, C.Y.; Lin, J.Y. Aqueous extract of Polygonum bistorta modulates proteostasis by ROS-induced ER stress in human hepatoma cells. Sci. Rep., 2017, 7, 41437.
[http://dx.doi.org/10.1038/srep41437 ] [PMID: 28134285]
[36]
Seervi, M.; Rani, A.; Sharma, A.K.; Santhosh Kumar, T.R. ROS mediated ER stress induces Bax-Bak dependent and independent apoptosis in response to Thioridazine. Biomed. Pharmacother., 2018, 106, 200-209.
[http://dx.doi.org/10.1016/j.biopha.2018.06.123 ] [PMID: 29960166]
[37]
Moon, D.O.; Park, S.Y.; Choi, Y.H.; Ahn, J.S.; Kim, G.Y. Guggulsterone sensitizes hepatoma cells to TRAIL-induced apoptosis through the induction of CHOP-dependent DR5: involvement of ROS-dependent ER-stress. Biochem. Pharmacol., 2011, 82(11), 1641-1650.
[http://dx.doi.org/10.1016/j.bcp.2011.08.019 ] [PMID: 21903093]
[38]
Yamaguchi, H.; Wang, H.G. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J. Biol. Chem., 2004, 279(44), 45495-45502.
[http://dx.doi.org/10.1074/jbc.M406933200 ] [PMID: 15322075]
[39]
Goldman, E.H.; Chen, L.; Fu, H. Activation of apoptosis signal-regulating kinase 1 by reactive oxygen species through dephosphorylation at serine 967 and 14-3-3 dissociation. J. Biol. Chem., 2004, 279(11), 10442-10449.
[http://dx.doi.org/10.1074/jbc.M311129200 ] [PMID: 14688258]

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