Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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MHY2251, a New SIRT1 Inhibitor, Induces Apoptosis via JNK/p53 Pathway in HCT116 Human Colorectal Cancer Cells

  • Yong Jung, Kang (Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University) ;
  • Young Hoon, Kwon (Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University) ;
  • Jung Yoon, Jang (Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University) ;
  • Jun Ho, Lee (Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University) ;
  • Sanggwon, Lee (Department of Manufacturing Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University) ;
  • Yujin, Park (Department of Manufacturing Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University) ;
  • Hyung Ryong, Moon (Department of Manufacturing Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University) ;
  • Hae Young, Chung (Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University) ;
  • Nam Deuk, Kim (Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University)
  • Received : 2022.03.25
  • Accepted : 2022.06.19
  • Published : 2023.01.01
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Abstract

Sirtuins (SIRTs) belong to the nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylase family. They are key regulators of cellular and physiological processes, such as cell survival, senescence, differentiation, DNA damage and stress response, cellular metabolism, and aging. SIRTs also influence carcinogenesis, making them potential targets for anticancer therapeutic strategies. In this study, we investigated the anticancer properties and underlying molecular mechanisms of a novel SIRT1 inhibitor, MHY2251, in human colorectal cancer (CRC) cells. MHY2251 reduced the viability of various human CRC cell lines, especially those with wild-type TP53. MHY2251 inhibited SIRT1 activity and SIRT1/2 protein expression, while promoting p53 acetylation, which is a target of SIRT1 in HCT116 cells. MHY2251 treatment triggered apoptosis in HCT116 cells. It increased the percentage of late apoptotic cells and the sub-G1 fraction (as detected by flow cytometric analysis) and induced DNA fragmentation. In addition, MHY2251 upregulated the expression of FasL and Fas, altered the ratio of Bax/Bcl-2, downregulated the levels of pro-caspase-8, -9, and -3 proteins, and induced subsequent poly(ADP-ribose) polymerase cleavage. The induction of apoptosis by MHY2251 was related to the activation of the caspase cascade, which was significantly attenuated by pre-treatment with Z-VAD-FMK, a pan-caspase inhibitor. Furthermore, MHY2251 stimulated the phosphorylation of c-Jun N-terminal kinase (JNK), and MHY2251-triggered apoptosis was blocked by pre-treatment with SP600125, a JNK inhibitor. This finding indicated the specific involvement of JNK in MHY2251-induced apoptosis. MHY2251 shows considerable potential as a therapeutic agent for targeting human CRC via the inhibition of SIRT1 and activation of JNK/p53 pathway.

Keywords

Acknowledgement

This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2021R1F1A1051265) and the Basic Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2018R1D1A1B07044648). We would like to thank the Aging Tissue Bank (http://grscicoll.org/institution/aging-tissue-bank) for providing research information.

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