Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Research Article

The Antitumor Effects of Icaritin Against Breast Cancer is Related to Estrogen Receptors

Author(s): Cheng-Cheng Tao, Yue Wu, Xiang Gao, Ling Qiao, Ying Yang, Fang Li, Jie Zou, Yu-Hao Wang, Shu-Yu Zhang, Chang-Long Li, Yuan-Yuan Zhang* and Xiao-Dong Sun*

Volume 21, Issue 1, 2021

Published on: 30 May, 2020

Page: [73 - 85] Pages: 13

DOI: 10.2174/1566524020666200530212440

Price: $65

Abstract

Objective: We aim to investigate the anticancer effects and mechanisms of icaritin against breast cancer.

Materials and Methods: Both estrogen receptor (ER) positive breast cancer cells MCF- 7 and ER-negative MDA-MB-231 cells were employed. We examined the effects of icaritin on the proliferation and migration by wound healing assay and transwell assay. Cell apoptosis and cell cycle of MCF-7 and MDA-MB-231 cells were analyzed using Flow cytometry. Cell autophagy of MCF-7 and MDA-MB-231 cells was assessed by western blotting, acridine orange staining and confocal microscopy. We also detected the expression of apoptosis-related genes by western blotting. In addition, an autophagy inhibitor was used to investigate whether cytoprotective autophagy was induced. Meanwhile, an ER inhibitor was utilized to explore whether ER was involved in autophagy.

Results: Icaritin inhibited the proliferation and migration, and induced cell cycle arrest of both MDA-MB-231 and MCF-7 cells. Icaritin significantly induced apoptosis of MDA-MB- 231 cells by activating caspase-3. And icaritin stimulated autophagy in MCF-7 cells, as evidenced by increased LC3II/LC3I, enhanced p62 degradation, the accumulation of endogenous LC3 puncta formation, and the increased autophagy flux. Icaritin induced autophagy through upregulating the phosphorylation of AMPK and ULK1. Chloroquine, an autophagy inhibitor, increased icaritin-induced apoptosis and proliferation inhibition of MCF-7 cells. Meanwhile, tamoxifen, an ER inhibitor, reversed icaritin-induced autophagy and proliferation inhibition of MCF-7 cells.

Conclusion: Our study demonstrated that the antitumor effects of icaritin against breast cancer are related to ER, which suggested that the status of ER should be considered in the clinical application of icaritin.

Keywords: Icaritin, estrogen receptor (ER), autophagy, apoptosis, AMPK, ULK1.

« Previous
[1]
Chen X, Song L, Hou Y, Li F. Reactive oxygen species induced by icaritin promote DNA strand breaks and apoptosis in human cervical cancer cells. Oncol Rep 2019; 41(2): 765-78.
[PMID: 30431140]
[2]
Wang ZQ, Weber N, Lou YJ, Proksch P. Prenylflavonoids as nonsteroidal phytoestrogens and related structure-activity relationships. ChemMedChem 2006; 1(4): 482-8.
[http://dx.doi.org/10.1002/cmdc.200500089] [PMID: 16892383]
[3]
Liu P, Jin X, Lv H, et al. Icaritin ameliorates carbon tetrachloride-induced acute liver injury mainly because of the antioxidative function through estrogen-like effects. In Vitro Cell Dev Biol Anim 2014; 50(10): 899-908.
[http://dx.doi.org/10.1007/s11626-014-9792-8] [PMID: 25148823]
[4]
Zhu DY, Lou YJ. Inducible effects of icariin, icaritin, and desmethylicaritin on directional differentiation of embryonic stem cells into cardiomyocytes in vitro. Acta Pharmacol Sin 2005; 26(4): 477-85.
[http://dx.doi.org/10.1111/j.1745-7254.2005.00076.x] [PMID: 15780198]
[5]
Liu L, Zhao Z, Lu L, et al. Icariin and icaritin ameliorated hippocampus neuroinflammation via inhibiting HMGB1-related pro-inflammatory signals in lipopolysaccharide-induced inflammation model in C57BL/6 J mice. Int Immunopharmacol 2019; 68: 95-105.
[http://dx.doi.org/10.1016/j.intimp.2018.12.055] [PMID: 30616172]
[6]
Zhou C, Gu J, Zhang G, et al. AMPK-autophagy inhibition sensitizes icaritin-induced anti-colorectal cancer cell activity. Oncotarget 2017; 8(9): 14736-47.
[http://dx.doi.org/10.18632/oncotarget.14718] [PMID: 28103582]
[7]
Pan XW, Li L, Huang Y, et al. Icaritin acts synergistically with epirubicin to suppress bladder cancer growth through inhibition of autophagy. Oncol Rep 2016; 35(1): 334-42.
[http://dx.doi.org/10.3892/or.2015.4335] [PMID: 26496799]
[8]
Han H, Xu B, Hou P, et al. Icaritin Sensitizes Human Glioblastoma Cells to TRAIL-Induced Apoptosis. Cell Biochem Biophys 2015; 72(2): 533-42.
[http://dx.doi.org/10.1007/s12013-014-0499-y] [PMID: 25577511]
[9]
Zhao H, Guo Y, Li S, et al. A novel anti-cancer agent Icaritin suppresses hepatocellular carcinoma initiation and malignant growth through the IL-6/Jak2/Stat3 pathway. Oncotarget 2015; 6(31): 31927-43.
[http://dx.doi.org/10.18632/oncotarget.5578] [PMID: 26376676]
[10]
Li S, Priceman SJ, Xin H, et al. Icaritin inhibits JAK/STAT3 signaling and growth of renal cell carcinoma. PLoS One 2013; 8(12)e81657
[http://dx.doi.org/10.1371/journal.pone.0081657] [PMID: 24324713]
[11]
Wu T, Wang S, Wu J, et al. Icaritin induces lytic cytotoxicity in extranodal NK/T-cell lymphoma. J Exp Clin Cancer Res 2015; 34: 17.
[http://dx.doi.org/10.1186/s13046-015-0133-x] [PMID: 25887673]
[12]
Tong JS, Zhang QH, Huang X, et al. Icaritin causes sustained ERK1/2 activation and induces apoptosis in human endometrial cancer cells. PLoS One 2011; 6(3)e16781
[http://dx.doi.org/10.1371/journal.pone.0016781] [PMID: 21408143]
[13]
Gao L, Chen M, Ouyang Y, et al. Icaritin induces ovarian cancer cell apoptosis through activation of p53 and inhibition of Akt/mTOR pathway. Life Sci 2018; 202: 188-94.
[http://dx.doi.org/10.1016/j.lfs.2018.03.059] [PMID: 29625193]
[14]
Wang X, Zheng N, Dong J, Wang X, Liu L, Huang J. Estrogen receptor-α36 is involved in icaritin induced growth inhibition of triple-negative breast cancer cells. J Steroid Biochem Mol Biol 2017; 171: 318-27.
[http://dx.doi.org/10.1016/j.jsbmb.2017.05.009] [PMID: 28529129]
[15]
Sun L, Peng Q, Qu L, Gong L, Si J. Anticancer agent icaritin induces apoptosis through caspase-dependent pathways in human hepatocellular carcinoma cells. Mol Med Rep 2015; 11(4): 3094-100.
[http://dx.doi.org/10.3892/mmr.2014.3007] [PMID: 25434584]
[16]
Liu Y, Shi L, Liu Y, et al. Activation of PPARγ mediates icaritin-induced cell cycle arrest and apoptosis in glioblastoma multiforme. Biomed Pharmacother 2018; 100: 358-66.
[http://dx.doi.org/10.1016/j.biopha.2018.02.006] [PMID: 29453045]
[17]
Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagyAutophagy 2016 ; 12: pp. 1-222..
[18]
Efeyan A, Comb WC, Sabatini DM. Nutrient-sensing mechanisms and pathways. Nature 2015; 517(7534): 302-10.
[http://dx.doi.org/10.1038/nature14190] [PMID: 25592535]
[19]
He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43: 67-93.
[http://dx.doi.org/10.1146/annurev-genet-102808-114910] [PMID: 19653858]
[20]
Fulda S, Kögel D. Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy. Oncogene 2015; 34(40): 5105-13.
[http://dx.doi.org/10.1038/onc.2014.458] [PMID: 25619832]
[21]
Denton D, Kumar S. Autophagy-dependent cell death. Cell Death Differ 2019; 26(4): 605-16.
[http://dx.doi.org/10.1038/s41418-018-0252-y] [PMID: 30568239]
[22]
Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A. Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ 2007; 14(3): 500-10.
[http://dx.doi.org/10.1038/sj.cdd.4402039] [PMID: 16990848]
[23]
Cook KL, Shajahan AN, Clarke R. Autophagy and endocrine resistance in breast cancer. Expert Rev Anticancer Ther 2011; 11(8): 1283-94.
[http://dx.doi.org/10.1586/era.11.111] [PMID: 21916582]
[24]
Sui X, Chen R, Wang Z, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis 2013; 4: e838-.
[http://dx.doi.org/10.1038/cddis.2013.350] [PMID: 24113172]
[25]
Marino M, Galluzzo P, Ascenzi P. Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics 2006; 7(8): 497-508.
[http://dx.doi.org/10.2174/138920206779315737] [PMID: 18369406]
[26]
Dey P, Barros RPA, Warner M, Ström A, Gustafsson JÅ. Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS. J Mol Endocrinol 2013; 51(3): T61-74.
[http://dx.doi.org/10.1530/JME-13-0150] [PMID: 24031087]
[27]
Sukocheva OA. Estrogen, estrogen receptors, and hepatocellular carcinoma: Are we there yet? World J Gastroenterol 2018; 24(1): 1-4.
[http://dx.doi.org/10.3748/wjg.v24.i1.1] [PMID: 29358876]
[28]
Bonkhoff H. Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression. Prostate 2018; 78(1): 2-10.
[http://dx.doi.org/10.1002/pros.23446] [PMID: 29094395]
[29]
Kyriakidis I, Papaioannidou P. Estrogen receptor beta and ovarian cancer: a key to pathogenesis and response to therapy. Arch Gynecol Obstet 2016; 293(6): 1161-8.
[http://dx.doi.org/10.1007/s00404-016-4027-8] [PMID: 26861465]
[30]
Nguyen-Vu T, Wang J, Mesmar F, et al. Estrogen receptor beta reduces colon cancer metastasis through a novel miR-205 - PROX1 mechanism. Oncotarget 2016; 7(27): 42159-71.
[http://dx.doi.org/10.18632/oncotarget.9895] [PMID: 27283988]
[31]
Tang W, Liu R, Yan Y, et al. Expression of estrogen receptors and androgen receptor and their clinical significance in gastric cancer. Oncotarget 2017; 8(25): 40765-77.
[http://dx.doi.org/10.18632/oncotarget.16582] [PMID: 28388558]
[32]
Kokabu T, Mori T, Matsushima H, et al. Antitumor effect of XCT790, an ERRα inverse agonist, on ERα-negative endometrial cancer cells. Cell Oncol (Dordr) 2019; 42(2): 223-35.
[http://dx.doi.org/10.1007/s13402-019-00423-5] [PMID: 30706380]
[33]
Tiong CT, Chen C, Zhang SJ, et al. A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERα protein. Carcinogenesis 2012; 33(5): 1089-97.
[http://dx.doi.org/10.1093/carcin/bgs110] [PMID: 22345291]
[34]
EH L. American society of health-system pharmacists. J Clin Pharm Ther 2011; 36: 159.
[35]
Boroumand M, Ghaedi M, Mohammadtaghvaei N, et al. Association of estrogen receptor α gene polymorphism with the presence of coronary artery disease documented by coronary angiography. Clin Biochem 2009; 42(9): 835-9.
[http://dx.doi.org/10.1016/j.clinbiochem.2009.01.005] [PMID: 19318036]
[36]
Dieli-Conwright CM, Spektor TM, Rice JC, Todd SE. Oestradiol and SERM treatments influence oestrogen receptor coregulator gene expression in human skeletal muscle cells. Acta Physiol (Oxf) 2009; 197(3): 187-96.
[http://dx.doi.org/10.1111/j.1748-1716.2009.01997.x] [PMID: 19432593]
[37]
Tang Y, Min Z, Xiang X-J, et al. Estrogen-related receptor alpha is involved in Alzheimer’s disease-like pathology. Exp Neurol 2018; 305: 89-96.
[http://dx.doi.org/10.1016/j.expneurol.2018.04.003] [PMID: 29641978]
[38]
de Lemos ML. Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann Pharmacother 2001; 35(9): 1118-21.
[http://dx.doi.org/10.1345/aph.10257] [PMID: 11573864]
[39]
Liang XH, Kleeman LK, Jiang HH, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 1998; 72(11): 8586-96.
[http://dx.doi.org/10.1128/JVI.72.11.8586-8596.1998] [PMID: 9765397]
[40]
Wirawan E, Vande Walle L, Kersse K, et al. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria Cell Death Dis 2010; 1e18
[http://dx.doi.org/10.1038/cddis.2009.16] [PMID: 21364619]
[41]
Radoshevich L, Murrow L, Chen N, et al. ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death. Cell 2010; 142(4): 590-600.
[http://dx.doi.org/10.1016/j.cell.2010.07.018] [PMID: 20723759]
[42]
Rubinstein AD, Eisenstein M, Ber Y, Bialik S, Kimchi A. The autophagy protein Atg12 associates with antiapoptotic Bcl-2 family members to promote mitochondrial apoptosis. Mol Cell 2011; 44(5): 698-709.
[http://dx.doi.org/10.1016/j.molcel.2011.10.014] [PMID: 22152474]
[43]
Yousefi S, Perozzo R, Schmid I, et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 2006; 8(10): 1124-32.
[http://dx.doi.org/10.1038/ncb1482] [PMID: 16998475]
[44]
Yin X, Cao L, Peng Y, et al. A critical role for UVRAG in apoptosis. Autophagy 2011; 7(10): 1242-4.
[http://dx.doi.org/10.4161/auto.7.10.16507] [PMID: 21606679]
[45]
Crighton D, Wilkinson S, Syed N, et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis Cell 2006; 126: 0-134
[46]
He H, Sinha I, Fan R, et al. c-Jun/AP-1 overexpression reprograms ERα signaling related to tamoxifen response in ERα-positive breast cancer. Oncogene 2018; 37(19): 2586-600.
[http://dx.doi.org/10.1038/s41388-018-0165-8] [PMID: 29467493]
[47]
Ma R, Karthik G-M, Lövrot J, et al. Estrogen receptor β as a therapeutic target in breast cancer stem cells. J Natl Cancer Inst 2017; 109(3): 1-14.
[http://dx.doi.org/10.1093/jnci/djw236] [PMID: 28376210]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy