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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Research Article

Dehydrocostus Lactone Induces Apoptosis and Cell Cycle Arrest through Regulation of JAK2/STAT3/PLK1 Signaling Pathway in Human Esophageal Squamous Cell Carcinoma Cells

Author(s): Ganghua Yang, Binwu Sheng, Ruixiang Li, Qinhong Xu, Lei Zhang* and Zhengyang Lu*

Volume 22, Issue 9, 2022

Page: [1742 - 1752] Pages: 11

DOI: 10.2174/1871520621666210805142200

Price: $65

Abstract

Background: Dehydrocostus lactone (DEH), one of the sesquiterpene lactones, has shown extensive pharmaceutical activities, including anti-cancer activity. However, its effects on human esophageal squamous cell carcinoma (ESCC) cells are still unknown.

Objective: To investigate the effect of DEH on ESCC cells and the underling molecular mechanisms.

Methods: The cell proliferation was tested using CCK-8 and colony formation assay. Apoptosis was analyzed by flow cytometry, hoechst staining and caspase-3 activity assay. Cell cycle was analyzed by flow cytometry. IL-6 (STAT3 activator) was used to activate JAK2/STAT3 pathway. Immunofluorescence assay was performed to detect intracellular location of STAT3. SiRNA transfection was performed to knock down the expression of PLK1. The protein expression was analyzed by western blotting assay.

Result: DHE treatment significantly reduced the viability of ESCC cells through apoptosis induction and cell cycle arrest. Furthermore, DHE treatment significantly inhibited the phosphorylation of JAK2 and STAT3. IF assay showed that the distribution of STAT3 in the nucleus was decreased by DHE treatment. In addition, coculture with IL-6 significantly prevented the inhibition of phosphorylation of JAK2 and STAT3 by DHE treatment and partly reversed the effect of DHE on ESCC cells. Moreover, DHE treatment significantly down-regulated the expression of PLK1, which was partly reversed by IL-6 coculture. Finally, knock down of PLK1 using siRNA reduced the viability of ESCC cells and induced apoptosis and cell cycle arrest

Conclusion: Our study demonstrated that DHE has a potent anti-cancer effect on ESCC cells through apoptosis induction and cell cycle arrest via JAK2/STAT3/PLK signaling pathway.

Keywords: Dehydrocostus lactone, apoptosis, cell cycle arrest, esophageal squamous cell carcinoma, STAT3, PLK1.

Graphical Abstract
[1]
Lin, Y.; Totsuka, Y.; He, Y.; Kikuchi, S.; Qiao, Y.; Ueda, J.; Wei, W.; Inoue, M.; Tanaka, H. Epidemiology of esophageal cancer in Japan and China. J. Epidemiol., 2013, 23(4), 233-242.
[http://dx.doi.org/10.2188/jea.JE20120162] [PMID: 23629646]
[2]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[3]
Abnet, C.C.; Arnold, M.; Wei, W.Q. Epidemiology of esophageal squamous cell carcinoma. Gastroentero., 2018, 154(2), 360-373.
[http://dx.doi.org/10.1053/j.gastro.2017.08.023] [PMID: 28823862]
[4]
Codipilly, D.C.; Qin, Y.; Dawsey, S.M.; Kisiel, J.; Topazian, M.; Ahlquist, D.; Iyer, P.G. Screening for esophageal squamous cell carcinoma: Recent advances. Gastrointest. Endosc., 2018, 88(3), 413-426.
[http://dx.doi.org/10.1016/j.gie.2018.04.2352] [PMID: 29709526]
[5]
Igelmann, S.; Neubauer, H.A.; Ferbeyre, G. STAT3 and STAT5 activation in solid cancers. Cancers (Basel), 2019, 11(10), E1428.
[http://dx.doi.org/10.3390/cancers11101428] [PMID: 31557897]
[6]
Guanizo, A.C.; Fernando, C.D.; Garama, D.J.; Gough, D.J. STAT3: a multifaceted oncoprotein. Growth Factors, 2018, 36(1-2), 1-14.
[http://dx.doi.org/10.1080/08977194.2018.1473393] [PMID: 29873274]
[7]
Liu, Z.; Sun, Q.; Wang, X. PLK1, A potential target for cancer therapy. Transl. Oncol., 2017, 10(1), 22-32.
[http://dx.doi.org/10.1016/j.tranon.2016.10.003] [PMID: 27888710]
[8]
Colicino, E.G.; Hehnly, H. Regulating a key mitotic regulator, polo-like kinase 1 (PLK1). Cytoskeleton (Hoboken), 2018, 75(11), 481-494.
[http://dx.doi.org/10.1002/cm.21504] [PMID: 30414309]
[9]
Elsayed, I.; Wang, X. PLK1 inhibition in cancer therapy: potentials and challenges. Future Med. Chem., 2019, 11(12), 1383-1386.
[http://dx.doi.org/10.4155/fmc-2019-0084] [PMID: 31298578]
[10]
Ren, X.; Liu, J.; Hu, L.; Liu, Q.; Wang, D.; Ning, X. Caffeic acid phenethyl ester inhibits the proliferation of HEp2 cells by regulating Stat3/Plk1 pathway and inducing S phase arrest. Biol. Pharm. Bull., 2019, 42(10), 1689-1693.
[http://dx.doi.org/10.1248/bpb.b19-00315] [PMID: 31366853]
[11]
Li, Q.; Wang, Z.; Xie, Y.; Hu, H. Antitumor activity and mechanism of costunolide and dehydrocostus lactone: Two natural sesquiterpene lactones from the Asteraceae family. Biomed. Pharmacother. Biomed. Pharmacotherapie, 2020, 125, 109955.
[12]
Dong, S.; Ma, L.Y.; Liu, Y.T.; Yu, M.; Jia, H.M.; Zhang, H.W.; Yu, C.Y.; Zou, Z.M. Pharmacokinetics of costunolide and dehydrocostuslactone after oral administration of Radix aucklandiae extract in normal and gastric ulcer rats. J. Asian Nat. Prod. Res., 2018, 20(11), 1055-1063.
[http://dx.doi.org/10.1080/10286020.2018.1489379] [PMID: 30130142]
[13]
Zhou, Q.; Zhang, W.X.; He, Z.Q.; Wu, B.S.; Shen, Z.F.; Shang, H.T.; Chen, T.; Wang, Q.; Chen, Y.G.; Han, S.T. The possible anti-inflammatory effect of dehydrocostus lactone on dss-induced colitis in mice. Evidence-based complementary and alternative medicine: eCAM, 2020, , 2020. 5659738
[14]
Cai, H.; Qin, X.; Yang, C. Dehydrocostus lactone suppresses proliferation of human chronic myeloid leukemia cells through Bcr/Abl-JAK/STAT signaling pathways. J. Cell. Biochem., 2017, 118(10), 3381-3390.
[http://dx.doi.org/10.1002/jcb.25994] [PMID: 28300289]
[15]
Lin, X.; Peng, Z.; Su, C. Potential anti-cancer activities and mechanisms of costunolide and dehydrocostuslactone. Int. J. Mol. Sci., 2015, 16(5), 10888-10906.
[http://dx.doi.org/10.3390/ijms160510888] [PMID: 25984608]
[16]
Wang, J.; Yu, Z.; Wang, C.; Tian, X.; Huo, X.; Wang, Y.; Sun, C.; Feng, L.; Ma, J.; Zhang, B.; Yang, Q.; Ma, X.; Xu, Y. Dehydrocostus lactone, a natural sesquiterpene lactone, suppresses the biological characteristics of glioma, through inhibition of the NF-κB/COX-2 signaling pathway by targeting IKKβ. Am. J. Cancer Res., 2017, 7(6), 1270-1284.
[PMID: 28670490]
[17]
Oh, G.S.; Pae, H.O.; Chung, H.T.; Kwon, J.W.; Lee, J.H.; Kwon, T.O.; Kwon, S.Y.; Chon, B.H.; Yun, Y.G. Dehydrocostus lactone enhances tumor necrosis factor-alpha-induced apoptosis of human leukemia HL-60 cells. Immunopharmacol. Immunotoxicol., 2004, 26(2), 163-175.
[http://dx.doi.org/10.1081/IPH-120037712] [PMID: 15209353]
[18]
Zhang, R.; Hao, J.; Wu, Q.; Guo, K.; Wang, C.; Zhang, W.K.; Liu, W.; Wang, Q.; Yang, X. Dehydrocostus lactone inhibits cell proliferation and induces apoptosis by PI3K/Akt/Bad and ERS signalling pathway in human laryngeal carcinoma. J. Cell. Mol. Med., 2020, 24(11), 6028-6042.
[http://dx.doi.org/10.1111/jcmm.15131] [PMID: 32319208]
[19]
Sheng, W.; Mao, H.; Wang, C.; Yang, N.; Zhang, Z.; Han, J. Dehydrocostus lactone enhances chemotherapeutic potential of doxorubicin in lung cancer by inducing cell death and limiting metastasis. Med. Sci. Monit., 2018, 24, 7850-7861.
[http://dx.doi.org/10.12659/MSM.911410] [PMID: 30388099]
[20]
Dong, G.Z.; Shim, A.R.; Hyeon, J.S.; Lee, H.J.; Ryu, J.H. Inhibition of Wnt/β-catenin pathway by dehydrocostus lactone and costunolide in colon cancer cells. Phytother. Res., 2015, 29(5), 680-686.
[http://dx.doi.org/10.1002/ptr.5299] [PMID: 25625870]
[21]
Johnson, D.E.; O’Keefe, R.A.; Grandis, J.R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol., 2018, 15(4), 234-248.
[http://dx.doi.org/10.1038/nrclinonc.2018.8] [PMID: 29405201]
[22]
Ko, H.; Lee, J.H.; Kim, H.S.; Kim, T.; Han, Y.T.; Suh, Y.G.; Chun, J.; Kim, Y.S.; Ahn, K.S. Novel Galiellalactone Analogues Can Target STAT3 Phosphorylation and Cause Apoptosis in Triple-Negative Breast Cancer. Biomolecules, 2019, 9(5), E170.
[http://dx.doi.org/10.3390/biom9050170] [PMID: 31058868]
[23]
Zhao, C.; Wang, W.; Yu, W.; Jou, D.; Wang, Y.; Ma, H.; Xiao, H.; Qin, H.; Zhang, C.; Lü, J.; Li, S.; Li, C.; Lin, J.; Lin, L. A novel small molecule STAT3 inhibitor, LY5, inhibits cell viability, colony formation, and migration of colon and liver cancer cells. Oncotarget, 2016, 7(11), 12917-12926.
[http://dx.doi.org/10.18632/oncotarget.7338] [PMID: 26883202]
[24]
Ji, Y.; Liu, Y.; Xue, N.; Du, T.; Wang, L.; Huang, R.; Li, L.; Yan, C.; Chen, X. Cryptotanshinone inhibits esophageal squamous-cell carcinoma in vitro and in vivo through the suppression of STAT3 activation. OncoTargets Ther., 2019, 12, 883-896.
[http://dx.doi.org/10.2147/OTT.S187777] [PMID: 30774375]
[25]
Liu, Y.; Wang, X.; Zeng, S.; Zhang, X.; Zhao, J.; Zhang, X.; Chen, X.; Yang, W.; Yang, Y.; Dong, Z.; Zhu, J.; Xu, X.; Tian, F. The natural polyphenol curcumin induces apoptosis by suppressing STAT3 signaling in esophageal squamous cell carcinoma. J. Exp. Clin. Cancer Res., 2018, 37(1), 303.
[http://dx.doi.org/10.1186/s13046-018-0959-0] [PMID: 30518397]
[26]
Cao, Y.Y.; Yu, J.; Liu, T.T.; Yang, K.X.; Yang, L.Y.; Chen, Q.; Shi, F.; Hao, J.J.; Cai, Y.; Wang, M.R.; Lu, W.H.; Zhang, Y. Plumbagin inhibits the proliferation and survival of esophageal cancer cells by blocking STAT3-PLK1-AKT signaling. Cell Death Dis., 2018, 9(2), 17.
[http://dx.doi.org/10.1038/s41419-017-0068-6] [PMID: 29339720]
[27]
Lin, C.C.; Su, W.C.; Yen, C.J.; Hsu, C.H.; Su, W.P.; Yeh, K.H.; Lu, Y.S.; Cheng, A.L.; Huang, D.C.; Fritsch, H.; Voss, F.; Taube, T.; Yang, J.C. A phase I study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies. Br. J. Cancer, 2014, 110(10), 2434-2440.
[http://dx.doi.org/10.1038/bjc.2014.195] [PMID: 24755882]
[28]
Bowles, D.W.; Diamond, J.R.; Lam, E.T.; Weekes, C.D.; Astling, D.P.; Anderson, R.T.; Leong, S.; Gore, L.; Varella-Garcia, M.; Vogler, B.W.; Keysar, S.B.; Freas, E.; Aisner, D.L.; Ren, C.; Tan, A.C.; Wilhelm, F.; Maniar, M.; Eckhardt, S.G.; Messersmith, W.A.; Jimeno, A. Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies. Clin. Cancer Res., 2014, 20(6), 1656-1665.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-2506] [PMID: 24493827]
[29]
Zhao, C.; Gong, L.; Li, W.; Chen, L. Overexpression of Plk1 promotes malignant progress in human esophageal squamous cell carcinoma. J. Cancer Res. Clin. Oncol., 2010, 136(1), 9-16.
[http://dx.doi.org/10.1007/s00432-009-0630-4] [PMID: 19572149]
[30]
Feng, Y.B.; Lin, D.C.; Shi, Z.Z.; Wang, X.C.; Shen, X.M.; Zhang, Y.; Du, X.L.; Luo, M.L.; Xu, X.; Han, Y.L.; Cai, Y.; Zhang, Z.Q.; Zhan, Q.M.; Wang, M.R. Overexpression of PLK1 is associated with poor survival by inhibiting apoptosis via enhancement of survivin level in esophageal squamous cell carcinoma. Int. J. Cancer, 2009, 124(3), 578-588.
[http://dx.doi.org/10.1002/ijc.23990] [PMID: 19004025]
[31]
Gu, M.M.; Li, M.; Gao, D.; Liu, L.H.; Lang, Y.; Yang, S.M.; Ou, H.; Huang, B.; Zhou, P.K.; Shang, Z.F. The vanillin derivative 6-bromine-5-hydroxy-4-methoxybenzaldehyde induces aberrant mitotic progression and enhances radio-sensitivity accompanying suppression the expression of PLK1 in esophageal squamous cell carcinoma. Toxicol. Appl. Pharmacol., 2018, 348, 76-84.
[http://dx.doi.org/10.1016/j.taap.2018.04.021] [PMID: 29679654]
[32]
Zhang, Y.; Du, X.L.; Wang, C.J.; Lin, D.C.; Ruan, X.; Feng, Y.B.; Huo, Y.Q.; Peng, H.; Cui, J.L.; Zhang, T.T.; Wang, Y.Q.; Zhang, H.; Zhan, Q.M.; Wang, M.R. Reciprocal activation between PLK1 and Stat3 contributes to survival and proliferation of esophageal cancer cells. Gastroenterol. 2012, 142(3), 521-530.e3.
[http://dx.doi.org/10.1053/j.gastro.2011.11.023] [PMID: 22108192]

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