Top

Published in:

01-01-2015 | Original Paper

(−)-Epigallocatechin-3-gallate induces cancer cell apoptosis via acetylation of amyloid precursor protein

Authors: Qian Hu, Xiang Chang, Rong Yan, Cuiping Rong, Cong Yang, Shuyi Cheng, Xiaoqiong Gu, Herui Yao, Xueqin Hou, Yousheng Mo, Luguang Zhao, Yunbo Chen, Xiaoxiao Dinlin, Qi Wang, Shuhuan Fang

Published in: Medical Oncology | Issue 1/2015

Abstract

Epigenetic modifications are involved in cancer pathogenesis, and HDACis are considered potential therapeutic agents. We and others have shown the inhibitory activity of EGCG on HDAC1. But little is known about the effect of EGCG as on epigenetic regulation in cancer. Here, we try to demonstrate that EGCG acts as an HDACi downregulated APP expression, which was pathophysiologically upregulated in cancers and exerts a key role in cancer cell growth. We used PC-12 cells, SK-N-SH cells and primary tumor tissues for our analysis. Male 4-week-old athymic nude mice were used for heterotopic tumor growth assay. We employed Western blotting analysis to detect Bcl-2, Bax, APP, caspase-3, caspase-7, HDAC1 and H4Ac. We used AnnexinV-FITC and TUNEL staining for apoptosis detection. Tumor tissues were examined by immunohistochemical staining. We demonstrated that EGCG suppresses the growth of xenografted adrenal pheochromocytoma. Flow cytometry analysis and TUNEL staining showed that EGCG induced the apoptosis. Treatment with EGCG resulted in decrease in Bcl-2 but increase in Bax and activated caspase-3 and caspase-7. HDAC inhibitor EGCG leaded to hyperacetylated histone H4 by immunofluorescence. EGCG decreased APP levels by immunofluorescence staining and Western blot analysis. Silencing specific to HDAC1 leaded to caspase-3 and caspase-7 activation and cleavage. Our results are the first to demonstrate a functional interaction between EGCG and APP in suppression tumor growth, and provide a new epigenetic effects of EGCG on antitumor.

Available only for authorised users

Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet. 2008;40(7):897–903. doi:10.1038/ng.154.PubMedCentralPubMedCrossRef

Hoshino I, Matsubara H. Recent advances in histone deacetylase targeted cancer therapy. Surg Today. 2010;40(9):809–15. doi:10.1007/s00595-010-4300-6.PubMedCrossRef

Narlikar GJ, Fan HY, Kingston RE. Cooperation between complexes that regulate chromatin structure and transcription. Cell. 2002;108(4):475–87.PubMedCrossRef

Emanuele S, Lauricella M, Tesoriere G. Histone deacetylase inhibitors: apoptotic effects and clinical implications (Review). Int J Oncol. 2008;33(4):637–46.PubMed

Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6(1):38–51. doi:10.1038/nrc1779.PubMedCrossRef

Drexler HC, Euler M. Synergistic apoptosis induction by proteasome and histone deacetylase inhibitors is dependent on protein synthesis. Apoptosis. 2005;10(4):743–58. doi:10.1007/s10495-005-2942-4.PubMedCrossRef

Hadnagy A, Beaulieu R, Balicki D. Histone tail modifications and noncanonical functions of histones: perspectives in cancer epigenetics. Mol Cancer Ther. 2008;7(4):740–8. doi:10.1158/1535-7163.mct-07-2284.PubMedCrossRef

Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res. 2004;10(11):3839–52. doi:10.1158/1078-0432.ccr-03-0561.PubMedCrossRef

Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood. 2003;102(10):3765–74. doi:10.1182/blood-2003-03-0737.PubMedCrossRef

10.

Fandy TE, Shankar S, Ross DD, Sausville E, Srivastava RK. Interactive effects of HDAC inhibitors and TRAIL on apoptosis are associated with changes in mitochondrial functions and expressions of cell cycle regulatory genes in multiple myeloma. Neoplasia. 2005;7(7):646–57.PubMedCentralPubMedCrossRef

11.

Bar-Sela G, Jacobs KM, Gius D. Histone deacetylase inhibitor and demethylating agent chromatin compaction and the radiation response by cancer cells. Cancer J. 2007;13(1):65–9. doi:10.1097/PPO.0b013e31803c7565.PubMedCrossRef

12.

Jazirehi AR. Regulation of apoptosis-associated genes by histone deacetylase inhibitors: implications in cancer therapy. Anticancer Drugs. 2010;21(9):805–13. doi:10.1097/CAD.0b013e32833dad91.PubMedCrossRef

13.

Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, et al. Tea polyphenol (−)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 2003;63(22):7563–70.PubMed

14.

Liu M, Chen F, Sha L, Wang S, Tao L, Yao L, et al. (−)-Epigallocatechin-3-gallate ameliorates learning and memory deficits by adjusting the balance of TrkA/p75NTR signaling in APP/PS1 transgenic mice. Mol Neurobiol. 2014;49(3):1350–63. doi:10.1007/s12035-013-8608-2.PubMedCentralPubMedCrossRef

15.

Biasibetti R, Tramontina AC, Costa AP, Dutra MF, Quincozes-Santos A, Nardin P, et al. Green tea (−)epigallocatechin-3-gallate reverses oxidative stress and reduces acetylcholinesterase activity in a streptozotocin-induced model of dementia. Behav Brain Res. 2013;236(1):186–93. doi:10.1016/j.bbr.2012.08.039.PubMedCrossRef

16.

Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, et al. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci. 2005;25(38):8807–14. doi:10.1523/jneurosci.1521-05.2005.PubMedCrossRef

17.

Murrell JR, Hake AM, Quaid KA, Farlow MR, Ghetti B. Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene. Arch Neurol. 2000;57(6):885–7.PubMedCrossRef

18.

Murrell J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science. 1991;254(5028):97–9.PubMedCrossRef

19.

Botelho MG, Wang X, Arndt-Jovin DJ, Becker D, Jovin TM. Induction of terminal differentiation in melanoma cells on downregulation of beta-amyloid precursor protein. J Invest Dermatol. 2010;130(5):1400–10. doi:10.1038/jid.2009.296.PubMedCrossRef

20.

Hansel DE, Rahman A, Wehner S, Herzog V, Yeo CJ, Maitra A. Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res. 2003;63(21):7032–7.PubMed

21.

Meng JY, Kataoka H, Itoh H, Koono M. Amyloid beta protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo. Int J Cancer. 2001;92(1):31–9.PubMedCrossRef

22.

Takayama K, Tsutsumi S, Suzuki T, Horie-Inoue K, Ikeda K, Kaneshiro K, et al. Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res. 2009;69(1):137–42. doi:10.1158/0008-5472.can-08-3633.PubMedCrossRef

23.

Wirths O, Thelen KM, Lutjohann D, Falkai P, Bayer TA. Altered cholesterol metabolism in APP695-transfected neuroblastoma cells. Brain Res. 2007;1152:209–14. doi:10.1016/j.brainres.2007.03.029.PubMedCrossRef

24.

Pietrzik CU, Hoffmann J, Stober K, Chen CY, Bauer C, Otero DA, et al. From differentiation to proliferation: the secretory amyloid precursor protein as a local mediator of growth in thyroid epithelial cells. Proc Natl Acad Sci USA. 1998;95(4):1770–5.PubMedCentralPubMedCrossRef

25.

Venkataramani V, Rossner C, Iffland L, Schweyer S, Tamboli IY, Walter J, et al. Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid precursor protein. J Biol Chem. 2010;285(14):10678–89. doi:10.1074/jbc.M109.057836.PubMedCentralPubMedCrossRef

26.

Bradley-Whitman MA, Lovell MA. Epigenetic changes in the progression of Alzheimer’s disease. Mech Ageing Dev. 2013;134(10):486–95. doi:10.1016/j.mad.2013.08.005.PubMedCrossRef

27.

Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J. Epigenetic mechanisms in Alzheimer’s disease. Neurobiol Aging. 2011;32(7):1161–80. doi:10.1016/j.neurobiolaging.2010.08.017.PubMedCentralPubMedCrossRef

28.

Xu Z, Fang S, Zuo Y, Zhang Y, Cheng R, Wang Q, et al. Combination of pigment epithelium-derived factor with radiotherapy enhances the antitumor effects on nasopharyngeal carcinoma by downregulating vascular endothelial growth factor expression and angiogenesis. Cancer Sci. 2011;102(10):1789–98. doi:10.1111/j.1349-7006.2011.02013.x.PubMedCrossRef

29.

Chen S, Zhao Y, Gou WF, Zhao S, Takano Y, Zheng HC. The anti-tumor effects and molecular mechanisms of suberoylanilide hydroxamic acid (SAHA) on the aggressive phenotypes of ovarian carcinoma cells. PLoS One. 2013;8(11):e79781. doi:10.1371/journal.pone.0079781.PubMedCentralPubMedCrossRef

30.

Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74(4):609–19.PubMedCrossRef

31.

Yang F, Zhang L, Li J, Huang J, Wen R, Ma L, et al. Trichostatin A and 5-azacytidine both cause an increase in global histone H4 acetylation and a decrease in global DNA and H3K9 methylation during mitosis in maize. BMC Plant Biol. 2010;10:178. doi:10.1186/1471-2229-10-178.PubMedCentralPubMedCrossRef

32.

Buoso E, Lanni C, Schettini G, Govoni S, Racchi M. β-Amyloid precursor protein metabolism: focus on the functions and degradation of its intracellular domain. Pharmacol Res. 2010;62(4):308–17. doi:10.1016/j.phrs.2010.05.002.PubMedCrossRef

33.

Kojro E, Fahrenholz F. The non-amyloidogenic pathway: structure and function of α-secretases. Subcell Biochem. 2005;38:105–27.PubMedCrossRef

34.

Zhang H, Ma Q, Zhang YW, Xu H. Proteolytic processing of Alzheimer’s β-amyloid precursor protein. J Neurochem. 2012;120(Suppl 1):9–21. doi:10.1111/j.1471-4159.2011.07519.x.PubMedCentralPubMedCrossRef

35.

Selkoe DJ, Podlisny MB, Joachim CL, Vickers EA, Lee G, Fritz LC, et al. Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues. Proc Natl Acad Sci USA. 1988;85(19):7341–5.PubMedCentralPubMedCrossRef

36.

Ko SY, Lin SC, Chang KW, Wong YK, Liu CJ, Chi CW, et al. Increased expression of amyloid precursor protein in oral squamous cell carcinoma. Int J Cancer. 2004;111(5):727–32. doi:10.1002/ijc.20328.PubMedCrossRef

37.

Choi KC, Jung MG, Lee YH, Yoon JC, Kwon SH, Kang HB, et al. Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation. Cancer Res. 2009;69(2):583–92. doi:10.1158/0008-5472.can-08-2442.PubMedCrossRef

38.

Groh IA, Chen C, Luske C, Cartus AT, Esselen M. Plant polyphenols and oxidative metabolites of the herbal alkenylbenzene methyleugenol suppress histone deacetylase activity in human colon carcinoma cells. J Nutr Metab. 2013;2013:821082. doi:10.1155/2013/821082.PubMedCentralPubMedCrossRef

39.

Ishihama K, Yamakawa M, Semba S, Takeda H, Kawata S, Kimura S, et al. Expression of HDAC1 and CBP/p300 in human colorectal carcinomas. J Clin Pathol. 2007;60(11):1205–10. doi:10.1136/jcp.2005.029165.PubMedCentralPubMedCrossRef

40.

Stypula-Cyrus Y, Damania D, Kunte DP, Cruz MD, Subramanian H, Roy HK, et al. HDAC up-regulation in early colon field carcinogenesis is involved in cell tumorigenicity through regulation of chromatin structure. PLoS One. 2013;8(5):e64600. doi:10.1371/journal.pone.0064600.PubMedCentralPubMedCrossRef

41.

Theocharis S, Klijanienko J, Giaginis C, Rodriguez J, Jouffroy T, Girod A, et al. Histone deacetylase-1 and -2 expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival. J Oral Pathol Med. 2011;40(9):706–14. doi:10.1111/j.1600-0714.2011.01031.x.PubMedCrossRef

42.

Patra SK, Patra A, Dahiya R. Histone deacetylase and DNA methyltransferase in human prostate cancer. Biochem Biophys Res Commun. 2001;287(3):705–13. doi:10.1006/bbrc.2001.5639.PubMedCrossRef

43.

Noro R, Miyanaga A, Minegishi Y, Okano T, Seike M, Soeno C, et al. Histone deacetylase inhibitor enhances sensitivity of non-small-cell lung cancer cells to 5-FU/S-1 via down-regulation of thymidylate synthase expression and up-regulation of p21(waf1/cip1) expression. Cancer Sci. 2010;101(6):1424–30. doi:10.1111/j.1349-7006.2010.01559.x.PubMedCrossRef

44.

Lin HY, Chen CS, Lin SP, Weng JR. Targeting histone deacetylase in cancer therapy. Med Res Rev. 2006;26(4):397–413. doi:10.1002/med.20056.PubMedCrossRef

45.

Chang SC, Wooden SK, Nakaki T, Kim YK, Lin AY, Kung L, et al. Rat gene encoding the 78-kDa glucose-regulated protein GRP78: its regulatory sequences and the effect of protein glycosylation on its expression. Proc Natl Acad Sci USA. 1987;84(3):680–4.PubMedCentralPubMedCrossRef

46.

Yang Y, Turner RS, Gaut JR. The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Aβ40 and Aβ42 secretion. J Biol Chem. 1998;273(40):25552–5.PubMedCrossRef

Title: (−)-Epigallocatechin-3-gallate induces cancer cell apoptosis via acetylation of amyloid precursor protein
Authors: Qian Hu
Xiang Chang
Rong Yan
Cuiping Rong
Cong Yang
Shuyi Cheng
Xiaoqiong Gu
Herui Yao
Xueqin Hou
Yousheng Mo
Luguang Zhao
Yunbo Chen
Xiaoxiao Dinlin
Qi Wang
Shuhuan Fang
Publication date: 01-01-2015
Publisher: Springer US
Published in: Medical Oncology / Issue 1/2015
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI: https://doi.org/10.1007/s12032-014-0390-0

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

(−)-Epigallocatechin-3-gallate induces cancer cell apoptosis via acetylation of amyloid precursor protein

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2015

High-dose chemotherapy and auto-SCT for relapsed and refractory Hodgkin’s lymphoma patients refractory to first-line salvage chemotherapy but responsive to second-line salvage chemotherapy

Topo2A as a prognostic biomarker for patients with resectable esophageal squamous cell carcinomas

Sonic hedgehog–Gli1 signals promote epithelial–mesenchymal transition in ovarian cancer by mediating PI3K/AKT pathway

Effect of smoking on survival from non-small cell lung cancer: a retrospective Veterans’ Affairs Central Cancer Registry (VACCR) cohort analysis

Molecular spectrum of c-KIT and PDGFRA gene mutations in gastro intestinal stromal tumor: determination of frequency, distribution pattern and identification of novel mutations in Indian patients

Insulin-like growth factor pathway aberrations and gastric cancer; evaluation of prognostic significance and assessment of therapeutic potentials

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page