A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation

被引:55
|
作者
De, Umasankar [1 ]
Son, Ji Yeon [1 ]
Sachan, Richa [1 ]
Park, Yu Jin [1 ]
Kang, Dongwan [2 ]
Yoon, Kyungsil [3 ]
Lee, Byung Mu [1 ]
Kim, In Su [1 ]
Moon, Hyung Ryong [2 ]
Kim, Hyung Sik [1 ]
机构
[1] Sungkyunkwan Univ, Sch Pharm, 2066 Seobu Ro, Suwon 16419, South Korea
[2] Pusan Natl Univ, Coll Pharm, Busandaehak Ro 63 Beon Gil 2, Busan 46241, South Korea
[3] Natl Canc Ctr, Div Translat Sci, Comparat Biomed Res Branch, 323 Ilsandong Gu, Goyang Si 10408, South Korea
基金
新加坡国家研究基金会;
关键词
histone deacetylase inhibitor; MHY2256; p53; apoptosis; autophagy; Ishikawa; endometrial cancer; SIRT1; EXPRESSION; METABOLISM; CARCINOMA; APICIDIN; ARREST;
D O I
10.3390/ijms19092743
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We previously discovered a novel sirtuin (SIRT) inhibitor, MHY2256, that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. We investigated the anticancer activity of MHY2256 against hormone-related cancer, an endometrial cancer with a poor prognosis. The IC50 values of MHY2256 were shown to be much lower than those of salermide, a well-known SIRT inhibitor. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3, with similar effects to salermide. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. A detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced the number of cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers.
引用
收藏
页数:12
相关论文
共 50 条
  • [31] A New Histone Deacetylase Inhibitor, MHY219, Inhibits the Migration of Human Prostate Cancer Cells via HDAC1
    De, Umasankar
    Kundu, Soma
    Patra, Nabanita
    Ahn, Mee Young
    Ahn, Ji Hae
    Son, Ji Yeon
    Yoon, Jung Hyun
    Moon, Hyung Ryoung
    Lee, Byung Mu
    Kim, Hyung Sik
    BIOMOLECULES & THERAPEUTICS, 2015, 23 (05) : 434 - 441
  • [32] Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21Waf1/Cip1
    Zhao, Y
    Lu, SL
    Wu, LP
    Chai, GL
    Wang, HY
    Chen, YQ
    Sun, J
    Yu, Y
    Zhou, W
    Zheng, QH
    Wu, M
    Otterson, GA
    Zhu, WG
    MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (07) : 2782 - 2790
  • [33] Radiation induces autophagic cell death via the p53/DRAM signaling pathway in breast cancer cells
    Cui, Li
    Song, Zhiheng
    Liang, Bing
    Jia, Lili
    Ma, Shumei
    Liu, Xiaodong
    ONCOLOGY REPORTS, 2016, 35 (06) : 3639 - 3647
  • [34] Histone deacetylase inhibitors, valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p53 in ERG-positive prostate cancer cells
    Fortson, Wendell S.
    Kayarthodi, Shubhalaxmi
    Fujimura, Yasuo
    Xu, Huali
    Matthews, Roland
    Grizzle, William E.
    Rao, Veena N.
    Bhat, Ganapathy K.
    Reddy, E. Shyam P.
    INTERNATIONAL JOURNAL OF ONCOLOGY, 2011, 39 (01) : 111 - 119
  • [35] Histone deacetylase inhibitor MGCD0103 causes cell cycle arrest, apoptosis, and autophagy in liver cancer cells
    Liao, Bo
    Sun, Quan
    Yuan, Yufeng
    Yin, Yuchun
    Qiao, Jianguo
    Jiang, Ping
    JOURNAL OF CANCER, 2020, 11 (07): : 1915 - 1926
  • [36] A synthetic 2,3-diarylindole induces cell death via apoptosis and autophagy in A549 lung cancer cells
    Rukkijakan, Thanya
    Ngiwsara, Lukana
    Lirdprapamongkol, Kriengsak
    Svasti, Jisnuson
    Phetrak, Nared
    Chuawong, Pitak
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (09) : 2119 - 2123
  • [37] CG0006, a novel histone deacetylase inhibitor, induces breast cancer cell death via histone-acetylation and chaperone-disrupting pathways independent of ER status
    Kim, Hyun Mi
    Kim, Choung-Soo
    Lee, Je-Hwan
    Jang, Se Jin
    Hwang, Jung Jin
    Ro, Seonggu
    Hyun, Young-Lan
    Choi, Jene
    BREAST CANCER RESEARCH AND TREATMENT, 2011, 130 (02) : 365 - 375
  • [38] CG0006, a novel histone deacetylase inhibitor, induces breast cancer cell death via histone-acetylation and chaperone-disrupting pathways independent of ER status
    Hyun Mi Kim
    Choung-Soo Kim
    Je-Hwan Lee
    Se Jin Jang
    Jung Jin Hwang
    Seonggu Ro
    Young-Lan Hyun
    Jene Choi
    Breast Cancer Research and Treatment, 2011, 130 : 365 - 375
  • [39] Histone deacetylase inhibitor-mediated radiosensitization of human cancer cells: Class differences and the potential influence of p53
    Kim, IA
    Shin, JH
    Kim, IH
    Kim, JH
    Kim, JS
    Wu, HG
    Chie, EK
    Ha, SW
    Park, CI
    Kao, GD
    CLINICAL CANCER RESEARCH, 2006, 12 (03) : 940 - 949
  • [40] POH1 knockdown induces cancer cell apoptosis via p53 and Bim
    Chen, Shi-Lu
    CANCER RESEARCH, 2018, 78 (13)