Int J Biol Sci 2016; 12(12):1555-1567. doi:10.7150/ijbs.13833
Anticancer Effects of a New SIRT Inhibitor, MHY2256, against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding
1. College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeung-gu, Busan, 609-735, Republic of Korea;
2. School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon 440-746, Republic of Korea;
3. Department of Korean Medical Science, School of Korean Medicine and Korean Medicine Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea;
4. Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
The sirtuins (SIRTs), a family of NAD+-dependent class III histone deacetylase, are involved in various biological processes including cell survival, division, senescence, and metabolism via activation of the stress-response pathway. Recently, inhibition of SIRTs has been considered a promising anticancer strategy, but their precise mechanisms of action are not well understood. In particular, the relevance of p53 to SIRT-induced effects has not been fully elucidated. We investigated the anticancer effects of a novel SIRT inhibitor, MHY2256, and its efficacy was compared to that of salermide in MCF-7 (wild-type p53) and SKOV-3 (null-type p53) cells. Cell viability, SIRT1 enzyme activity, cell cycle regulation, apoptosis, and autophagic cell death were measured. We compared sensitivity to cytotoxicity in MCF-7 and SKOV-3 cells. MHY2256 significantly decreased the viability of MCF-7 (IC50, 4.8 μM) and SKOV-3 (IC50, 5.6 μM) cells after a 48 h treatment period. MHY2256 showed potent inhibition (IC50, 0.27 mM) against SIRT1 enzyme activity compared with nicotinamide (IC50, >1 mM). Moreover, expression of SIRT (1, 2, or 3) protein levels was significantly reduced by MHY2256 treatment in both MCF-7 and SKOV-3 cells. Flow cytometry analysis revealed that MHY2256 significantly induced cell cycle arrest in the G1 phase, leading to an effective increase in apoptotic cell death in MCF-7 and SKOV-3 cells. A significant increase in acetylated p53, a target protein of SIRT, was observed in MCF-7 cells after MHY2256 treatment. MHY2256 up-regulated LC3-II and induced autophagic cell death in MCF-7 cells. Furthermore, MHY2256 markedly inhibited tumor growth in a tumor xenograft model of MCF-7 cells. These results suggest that a new SIRT inhibitor, MHY2256, has anticancer activity through p53 acetylation in MCF-7 human breast cancer cells.
Keywords: SIRT inhibitor, MHY2256, MDM2, p53, apoptosis, autophagy.
Park EY, Woo Y, Kim SJ, Kim DH, Lee EK, De U, Kim KS, Lee J, Jung JH, Ha KT, Choi WS, Kim IS, Lee BM, Yoon S, Moon HR, Kim HS. Anticancer Effects of a New SIRT Inhibitor, MHY2256, against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding. Int J Biol Sci 2016; 12(12):1555-1567. doi:10.7150/ijbs.13833. Available from http://www.ijbs.com/v12p1555.htm