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.
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页数:12
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