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

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.

• 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
• Journal: Medical oncology (Northwood, London, England) (Med Oncol) Vol. 32 Issue 1 Pg. 390 (Jan 2015) ISSN: 1559-131X [Electronic] United States
• PMID: 25452172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Protein Precursor
• Anticarcinogenic Agents
• Histone Deacetylase Inhibitors
• Catechin
• epigallocatechin gallate

Topics

• Acetylation
• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Anticarcinogenic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Catechin (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Epigenesis, Genetic (drug effects)
• Flow Cytometry
• Fluorescent Antibody Technique
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Male
• Mice
• Mice, Nude
• Neoplasms, Experimental (drug therapy, pathology)
• Rats
• Xenograft Model Antitumor Assays