Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Caffeic Acid Phenethyl Ester Inhibits Ubiquitination and Degradation of p53 and Blocks Cervical Cancer Cell Growth

Author(s): Wei Li, Cong Yang, Zhongxiu Shi, Qingqing Long, Zhiying Cheng, Shan He, Jiahui Dong, Tao Liu and Chengcheng Wang*

Volume 23, Issue 9, 2023

Published on: 11 October, 2022

Page: [960 - 970] Pages: 11

DOI: 10.2174/1566524023666220829154716

Price: $65

Abstract

Background: In high-risk human papillomavirus (HR-HPV)-positive cervical cancer, E6-associated protein (E6AP), an E3 ubiquitin ligase, mediates the ubiquitination and proteasomal degradation of the tumor suppressor p53. Here, we addressed the question of whether caffeic acid phenethyl ester (CAPE), a natural product mainly derived from propolis, can disrupt the interaction between E6AP and p53, inhibit ubiquitination degradation of p53 and exhibit anti-cervical cancer activity.

Methods: The ability of CAPE to inhibit growth and to induce apoptosis was shown in HR-HPV-positive cervical cancer cell lines by performing CCK-8, colony formation and TUNEL assays. Apoptosis-related proteins were tested by western blotting. Coimmunoprecipitation, ubiquitination assay and protein stability assay were carried out to determine whether CAPE can disrupt the E6AP-p53 interaction and inhibit ubiquitination degradation of p53.

Results: Our results showed that CAPE inhibits the growth of HR-HPV-positive cervical cancer cells and induces the activation of apoptosis-related pathways. Importantly, CAPE inhibits E6AP expression and disrupts the interaction between E6AP and p53. It inhibits the ubiquitination of p53 and promotes its stabilization.

Conclusion: In summary, CAPE has a therapeutic effect on HPV-positive malignant cells, so further studies are needed to assess its clinical application.

Keywords: CAPE, Cervical, cancer, HPV, E6AP, p53

« Previous Next »
[1]
Sari AN, Bhargava P, Dhanjal JK, et al. Combination of Withaferin-A and CAPE provides superior anticancer potency: Bioinformatics and experimental evidence to their molecular targets and mechanism of action. Cancers 2020; 12(5): 1160.
[http://dx.doi.org/10.3390/cancers12051160] [PMID: 32380701]
[2]
Moore DH, Tian C, Monk BJ, Long HJ, Omura GA, Bloss JD. Prognostic factors for response to cisplatin based chemotherapy in advanced cervical carcinoma: A gynecologic oncology group study. Gynecol Oncol 2010; 116(1): 44-9.
[http://dx.doi.org/10.1016/j.ygyno.2009.09.006] [PMID: 19853287]
[3]
Wolford JE, Tewari KS. Rational design for cervical cancer therapeutics: Cellular and non-cellular based strategies on the horizon for recurrent, metastatic or refractory cervical cancer. Expert Opin Drug Discov 2018; 13(5): 445-57.
[http://dx.doi.org/10.1080/17460441.2018.1443074] [PMID: 29463131]
[4]
Shai A, Pitot HC, Lambert PF. E6-associated protein is required for human papillomavirus type 16 E6 to cause cervical cancer in mice. Cancer Res 2010; 70(12): 5064-73.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3307] [PMID: 20530688]
[5]
Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990; 63(6): 1129-36.
[http://dx.doi.org/10.1016/0092-8674(90)90409-8] [PMID: 2175676]
[6]
Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin protein ligase in the ubiquitination of p53. Cell 1993; 75(3): 495-505.
[http://dx.doi.org/10.1016/0092-8674(93)90384-3] [PMID: 8221889]
[7]
Ferenczy A, Franco E. Persistent human papillomavirus infection and cervical neoplasia. Lancet Oncol 2002; 3(1): 11-6.
[http://dx.doi.org/10.1016/S1470-2045(01)00617-9] [PMID: 11905599]
[8]
Bernard X, Robinson P, Nominé Y, et al. Proteasomal degradation of p53 by human papillomavirus E6 oncoprotein relies on the structural integrity of p53 core domain. PLoS One 2011; 6(10): e25981.
[http://dx.doi.org/10.1371/journal.pone.0025981] [PMID: 22046250]
[9]
Modi A, Singh M, Gutti G, et al. Benzothiazole derivative bearing amide moiety induces p53-mediated apoptosis in HPV16 positive cervical cancer cells. Invest New Drugs 2020; 38(4): 934-45.
[http://dx.doi.org/10.1007/s10637-019-00848-7] [PMID: 31432292]
[10]
Grunberger D, Banerjee R, Eisinger K, et al. Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia 1988; 44(3): 230-2.
[http://dx.doi.org/10.1007/BF01941717] [PMID: 2450776]
[11]
Balaha M, De Filippis B, Cataldi A, di Giacomo V. CAPE and neuroprotection: A review. Biomolecules 2021; 11(2): 176.
[http://dx.doi.org/10.3390/biom11020176] [PMID: 33525407]
[12]
Cui Z, Wang Q, Li D, et al. Icariin, formononetin and caffeic acid phenethyl ester inhibit feline calicivirus replication in vitro. Arch Virol 2021; 166(9): 2443-50.
[http://dx.doi.org/10.1007/s00705-021-05107-w] [PMID: 34173062]
[13]
Tolba MF, Omar HA, Azab SS, Khalifa AE, Abdel NAB, Abdel RSZ. Caffeic acid phenethyl ester: A review of its antioxidant activity, protective effects against ischemia reperfusion injury and drug adverse reactions. Crit Rev Food Sci Nutr 2016; 56(13): 2183-90.
[http://dx.doi.org/10.1080/10408398.2013.821967] [PMID: 25365228]
[14]
Ozturk G, Ginis Z, Akyol S, Erden G, Gurel A, Akyol O. The anticancer mechanism of caffeic acid phenethyl ester (CAPE): Review of melanomas, lung and prostate cancers. Eur Rev Med Pharmacol Sci 2012; 16(15): 2064-8.
[PMID: 23280020]
[15]
Xiang D, Wang D, He Y, et al. Caffeic acid phenethyl ester induces growth arrest and apoptosis of colon cancer cells via the β-catenin/T-cell factor signaling. Anticancer Drugs 2006; 17(7): 753-62.
[http://dx.doi.org/10.1097/01.cad.0000224441.01082.bb] [PMID: 16926625]
[16]
Chen MF, Wu CT, Chen YJ, Keng PC, Chen WC. Cell killing and radiosensitization by caffeic acid phenethyl ester (CAPE) in lung cancer cells. J Radiat Res (Tokyo) 2004; 45(2): 253-60.
[http://dx.doi.org/10.1269/jrr.45.253] [PMID: 15304968]
[17]
Omene CO, Wu J, Frenkel K. Caffeic Acid Phenethyl Ester (CAPE) derived from propolis, a honeybee product, inhibits growth of breast cancer stem cells. Invest New Drugs 2012; 30(4): 1279-88.
[http://dx.doi.org/10.1007/s10637-011-9667-8] [PMID: 21537887]
[18]
Motawi TK, Abdelazim SA, Darwish HA, Elbaz EM, Shouman SA. Modulation of tamoxifen cytotoxicity by caffeic acid phenethyl ester in MCF-7 breast cancer cells. Oxid Med Cell Longev 2016; 2016: 1-13.
[http://dx.doi.org/10.1155/2016/3017108] [PMID: 26697130]
[19]
Kabała DA, Rzepecka SA, Kubina R, et al. Comparison of two components of propolis: Caffeic Acid (CA) and Caffeic Acid Phenethyl Ester (CAPE) induce apoptosis and cell cycle arrest of breast cancer cells MDA-MB-231. Molecules 2017; 22(9): 1554.
[http://dx.doi.org/10.3390/molecules22091554] [PMID: 28926932]
[20]
Chen MJ, Chang WH, Lin CC, et al. Caffeic acid phenethyl ester induces apoptosis of human pancreatic cancer cells involving caspase and mitochondrial dysfunction. Pancreatology 2008; 8(6): 558-65.
[http://dx.doi.org/10.1159/000159214] [PMID: 18824880]
[21]
Rzepecka SA, Kabała DA, Moździerz A, et al. Caffeic Acid phenethyl ester and ethanol extract of propolis induce the complementary cytotoxic effect on triple negative breast cancer cell lines. Molecules 2015; 20(5): 9242-62.
[http://dx.doi.org/10.3390/molecules20059242] [PMID: 26007182]
[22]
Chiang EPI, Tsai SY, Kuo YH, et al. Caffeic acid derivatives inhibit the growth of colon cancer: Involvement of the PI3-K/Akt and AMPK signaling pathways. PLoS One 2014; 9(6): e99631.
[http://dx.doi.org/10.1371/journal.pone.0099631] [PMID: 24960186]
[23]
Carrasco LCE, Sánchez PY, Márquez RL, et al. A single dose of caffeic acid phenethyl ester prevents initiation in a medium term rat hepatocarcinogenesis model. World J Gastroenterol 2006; 12(42): 6779-85.
[http://dx.doi.org/10.3748/wjg.v12.i42.6779] [PMID: 17106925]
[24]
Chuu CP, Lin HP, Ciaccio MF, et al. Caffeic acid phenethyl ester suppresses the proliferation of human prostate cancer cells through inhibition of p70S6K and Akt signaling networks. Cancer Prev Res 2012; 5(5): 788-97.
[http://dx.doi.org/10.1158/1940-6207.CAPR-12-0004-T] [PMID: 22562408]
[25]
Kaushal JB, Bhatia R, Kanchan RK, et al. Repurposing niclosamide for targeting pancreatic cancer by inhibiting Hh/Gli non-canonical axis of Gsk3β. Cancers 2021; 13(13): 3105.
[http://dx.doi.org/10.3390/cancers13133105] [PMID: 34206370]
[26]
Xu X, Li C, Gao X, et al. Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders. Cell Res 2018; 28(1): 48-68.
[http://dx.doi.org/10.1038/cr.2017.132] [PMID: 29076503]
[27]
Peng H, Yang J, Li G, et al. Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress. Cell Res 2017; 27(5): 657-74.
[http://dx.doi.org/10.1038/cr.2017.40] [PMID: 28322253]
[28]
Patiño MCC, Soto RE, Arechaga OE, et al. Curcumin stabilizes p53 by interaction with NAD(P)H:quinone oxidoreductase 1 in tumor derived cell lines. Redox Biol 2020; 28: 101320.
[http://dx.doi.org/10.1016/j.redox.2019.101320] [PMID: 31526948]
[29]
Beaudenon S, Huibregtse JM. HPV E6, E6AP and cervical cancer. BMC Biochem 2008; 9(1): S4.
[http://dx.doi.org/10.1186/1471-2091-9-S1-S4] [PMID: 19007434]
[30]
Gonzalez RMJ, Fondevila MF, Fernandez U, et al. O-GlcNAcylated p53 in the liver modulates hepatic glucose production. Nat Commun 2021; 12(1): 5068.
[http://dx.doi.org/10.1038/s41467-021-25390-0] [PMID: 34417460]
[31]
Donehower LA, Harvey M, Slagle BL, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 1992; 356(6366): 215-21.
[http://dx.doi.org/10.1038/356215a0] [PMID: 1552940]
[32]
Miller JJ, Gaiddon C, Storr T. A balancing act: Using small molecules for therapeutic intervention of the p53 pathway in cancer. Chem Soc Rev 2020; 49(19): 6995-7014.
[http://dx.doi.org/10.1039/D0CS00163E] [PMID: 32869798]
[33]
Udomwan P, Pientong C, Tongchai P, et al. Proteomics analysis of andrographolide-induced apoptosis via the regulation of tumor suppressor p53 proteolysis in cervical cancer-derived human papillomavirus 16-positive cell lines. Int J Mol Sci 2021; 22(13): 6806.
[http://dx.doi.org/10.3390/ijms22136806] [PMID: 34202736]
[34]
Jimenez GS, Khan SH, Stommel JM, Wahl GM. p53 regulation by post-translational modification and nuclear retention in response to diverse stresses. Oncogene 1999; 18(53): 7656-65.
[http://dx.doi.org/10.1038/sj.onc.1203013] [PMID: 10618705]
[35]
Meek DW, Anderson CW. Posttranslational modification of p53: Cooperative integrators of function. Cold Spring Harb Perspect Biol 2009; 1(6): a000950.
[http://dx.doi.org/10.1101/cshperspect.a000950] [PMID: 20457558]
[36]
Bode AM, Dong Z. Post translational modification of p53 in tumorigenesis. Nat Rev Cancer 2004; 4(10): 793-805.
[http://dx.doi.org/10.1038/nrc1455] [PMID: 15510160]
[37]
Zhao X, Sun W, Ren Y, Lu Z. Therapeutic potential of p53 reactivation in cervical cancer. Crit Rev Oncol Hematol 2021; 157: 103182.
[http://dx.doi.org/10.1016/j.critrevonc.2020.103182] [PMID: 33276182]
[38]
Jain AK, Allton K, Duncan AD, Barton MC. TRIM24 is a p53 induced E3 ubiquitin ligase that undergoes ATM mediated phosphorylation and autodegradation during DNA damage. Mol Cell Biol 2014; 34(14): 2695-709.
[http://dx.doi.org/10.1128/MCB.01705-12] [PMID: 24820418]
[39]
Pal A, Young MA, Donato NJ. Emerging potential of therapeutic targeting of ubiquitin-specific proteases in the treatment of cancer. Cancer Res 2014; 74(18): 4955-66.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-1211] [PMID: 25172841]
[40]
Nag S, Qin J, Srivenugopal KS, Wang M, Zhang R. The MDM2-p53 pathway revisited. J Biomed Res 2013; 27(4): 254-71.
[http://dx.doi.org/10.7555/JBR.27.20130030] [PMID: 23885265]
[41]
Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004; 303(5659): 844-8.
[http://dx.doi.org/10.1126/science.1092472] [PMID: 14704432]
[42]
Hengstermann A, Linares LK, Ciechanover A, Whitaker NJ, Scheffner M. Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells. Proc Natl Acad Sci USA 2001; 98(3): 1218-23.
[http://dx.doi.org/10.1073/pnas.98.3.1218] [PMID: 11158620]
[43]
Wolyniec K, Shortt J, de Stanchina E, et al. E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis. Blood 2012; 120(4): 822-32.
[http://dx.doi.org/10.1182/blood-2011-10-387647] [PMID: 22689861]
[44]
Owais A, Mishra RK, Kiyokawa H. The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders. Cancers 2020; 12(8): 2108.
[http://dx.doi.org/10.3390/cancers12082108] [PMID: 32751183]
[45]
Huibregtse JM, Scheffner M, Howley PM. Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol Cell Biol 1993; 13(8): 4918-27.
[http://dx.doi.org/10.1128/mcb.13.8.4918-4927.1993] [PMID: 8393140]
[46]
Paul PJ, Raghu D, Chan AL, et al. Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP. Oncogene 2016; 35(48): 6235-45.
[http://dx.doi.org/10.1038/onc.2016.159] [PMID: 27641331]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy