EGCG induces lung cancer A549 cell apoptosis by regulating Ku70 acetylation.

Lung cancer is the leading cause of cancer-related death worldwide. (-)-Epigallocatechin-3-gallate (EGCG) is a potential chemopreventive and therapeutic agent for lung cancer. Induction of apoptosis was examined using Annexin V/PI double staining flow cytometry. Western blot analysis detected the protein expression of cleaved caspase-3, Bax and Bcl-xL. Co-immunoprecipitation was used to detect the interaction of Ku70-Bax and the acetylation status of Ku70. Treatment of A549 cells with EGCG-induced apoptosis via increased expression of cleaved caspase-3 and Bax, but decreased expression of Bcl-xL. EGCG upregulated the K70 acetylation status of A549 cells and downregulated the interaction of Bax-Ku70 in a concentration- and time-dependent manner. The apoptosis-promoting effect of EGCG on A549 cells was obviously weakened, along with strengthening of the Bax-Ku70 interaction, after pCDNA3.1(+)-Ku70 plasmid and pCDNA3.1(+)-Ku70539/542R plasmid transfection. Our results established a role of EGCG in inducing cell apoptosis by suppressing Bax activity. Regulating Ku70 acetylation by EGCG, that block the interaction between Ku70 and Bax, will result in lung cancer cell apoptosis.

[1]  Chia-Hung Chou,et al.  Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway , 2003, Oncogene.

[2]  Hongju Wu,et al.  Low-dose docetaxel combined with (-)-epigallocatechin-3-gallate inhibits angiogenesis and tumor growth in nude mice with gastric cancer xenografts. , 2012, Cancer biotherapy & radiopharmaceuticals.

[3]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[4]  Z. Y. Wang,et al.  Tea and cancer. , 1993, Journal of the National Cancer Institute.

[5]  Q. Gu,et al.  Role of Ku70 and Bax in epigallocatechin-3-gallate-induced apoptosis of A549 cells in vivo. , 2013, Oncology letters.

[6]  P. Yu,et al.  Anti-cancer activities of tea epigallocatechin-3-gallate in breast cancer patients under radiotherapy. , 2012, Current molecular medicine.

[7]  H. Mukhtar,et al.  Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-κB activation in normal human bronchial epithelial cells , 2007, Oncogene.

[8]  M. Sawada,et al.  Cytoprotective membrane-permeable peptides designed from the Bax-binding domain of Ku70 , 2003, Nature Cell Biology.

[9]  P. Johnston,et al.  Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent. , 2012, European journal of cancer.

[10]  Kyung-Chul Choi,et al.  EGCG suppresses prostate cancer cell growth modulating acetylation of androgen receptor by anti-histone acetyltransferase activity. , 2012, International journal of molecular medicine.

[11]  Yan Xu,et al.  Epigallocatechin gallate promotes p53 accumulation and activity via the inhibition of MDM2-mediated p53 ubiquitination in human lung cancer cells. , 2013, Oncology reports.

[12]  Litu Zhang,et al.  (−)-Epigallocatechingallate induces apoptosis in B lymphoma cells via caspase-dependent pathway and Bcl-2 family protein modulation , 2015, International journal of oncology.

[13]  K. Sugihara,et al.  Green tea polyphenol EGCG induces lipid-raft clustering and apoptotic cell death by activating protein kinase Cδ and acid sphingomyelinase through a 67 kDa laminin receptor in multiple myeloma cells. , 2012, The Biochemical journal.

[14]  Mi Hee Lee,et al.  Apoptosis of human fibrosarcoma HT-1080 cells by epigallocatechin-3-O-gallate via induction of p53 and caspases as well as suppression of Bcl-2 and phosphorylated nuclear factor-κB , 2010, Apoptosis.

[15]  John Calvin Reed,et al.  Antiapoptotic proteins. The bcl-2 and inhibitor of apoptosis protein families. , 2001, Cardiology clinics.

[16]  P. Sorensen,et al.  Inhibition of the Insulin-Like Growth Factor I Receptor by Epigallocatechin Gallate Blocks Proliferation and Induces the Death of Ewing Tumor Cells , 2010, Molecular Cancer Therapeutics.

[17]  M. Thun,et al.  American Cancer Society guidelines on nutrition and physical activity for cancer prevention , 2002, CA: a cancer journal for clinicians.

[18]  R. Ikeda,et al.  Green tea catechin, epigallocatechin-3-gallate, attenuates the cell viability of human non-small-cell lung cancer A549 cells via reducing Bcl-xL expression , 2014, Experimental and therapeutic medicine.

[19]  David A. Boothman,et al.  Ku70 suppresses the apoptotic translocation of Bax to mitochondria , 2003, Nature Cell Biology.

[20]  M. Thun,et al.  American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention: Reducing the Risk of Cancer With Healthy Food Choices and Physical Activity , 2002, CA: a cancer journal for clinicians.

[21]  Hidde Ploegh,et al.  Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. , 2004, Molecular cell.

[22]  Ioana Berindan-Neagoe,et al.  Early transcriptional pattern of angiogenesis induced by EGCG treatment in cervical tumour cells , 2012, Journal of cellular and molecular medicine.

[23]  Yan Tang,et al.  Epigallocatechin-3 gallate induces growth inhibition and apoptosis in human breast cancer cells through survivin suppression. , 2007, International journal of oncology.

[24]  Roland P. S. Kwok,et al.  Regulation of Ku70-Bax Complex in Cells , 2014, Journal of cell death.

[25]  Y. Lou,et al.  Topical applications of caffeine or (−)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Kuang-Chi Lai,et al.  (-)-Epigallocatechin gallate induced apoptosis in human adrenal cancer NCI-H295 cells through caspase-dependent and caspase-independent pathway. , 2009, Anticancer research.

[27]  H. Mukhtar,et al.  Ablation of either p21 or Bax prevents p53‐dependent apoptosis induced by green tea polyphenol epigallocatechin‐3‐gallate , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[28]  Chengping Hu,et al.  Tea polyphenols prevent lung from preneoplastic lesions and effect p53 and bcl-2 gene expression in rat lung tissues. , 2013, International journal of clinical and experimental pathology.

[29]  H. Mukhtar,et al.  Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-kappaB activation in normal human bronchial epithelial cells. , 2007, Oncogene.

[30]  F. Gao,et al.  Epigallocatechin gallate inhibits the growth of human lung cancer by directly targeting the EGFR signaling pathway. , 2014, Oncology reports.

[31]  Helgi I. Ingólfsson,et al.  The inhibitory effect of (-)-epigallocatechin gallate on activation of the epidermal growth factor receptor is associated with altered lipid order in HT29 colon cancer cells. , 2007, Cancer research.

[32]  K. Dong,et al.  Apoptosis induction effects of EGCG in laryngeal squamous cell carcinoma cells through telomerase repression , 2009, Archives of pharmacal research.