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Novel SIRT Inhibitor, MHY2256, Induces Cell Cycle Arrest, Apoptosis, and Autophagic Cell Death in HCT116 Human Colorectal Cancer Cells

Biomolecules & Therapeutics 2020년 28권 6호 p.561 ~ 568
김민정, 강영정, 성보경, Jang Jung-Yoon, 안유라, 오혜진, 최희정, 최인규, 임은옥, 문형룡, 정해영, 김남득,
소속 상세정보
김민정 ( Kim Min-Jeong ) - Pusan National University College of Pharmacy Department of Pharmacy
강영정 ( Kang Young-Jung ) - Pusan National University College of Pharmacy Department of Pharmacy
성보경 ( Sung Bo-Kyung ) - Pusan National University College of Pharmacy Department of Pharmacy
 ( Jang Jung-Yoon ) - Pusan National University College of Pharmacy Department of Pharmacy
안유라 ( Ahn Yu-Ra ) - Pusan National University College of Pharmacy Department of Pharmacy
오혜진 ( Oh Hye-Jin ) - Pusan National University College of Pharmacy Department of Pharmacy
최희정 ( Choi Hee-Jeong ) - Pusan National University College of Pharmacy Department of Pharmacy
최인규 ( Choi In-Kyu ) - Pusan National University College of Pharmacy Department of Pharmacy
임은옥 ( Im Eun-Ok ) - Pusan National University College of Pharmacy Department of Pharmacy
문형룡 ( Moon Hyung-Ryong ) - Pusan National University College of Pharmacy Department of Pharmacy
정해영 ( Chung Hae-Young ) - Pusan National University College of Pharmacy Department of Pharmacy
김남득 ( Kim Nam-Deuk ) - Pusan National University College of Pharmacy Department of Pharmacy

Abstract


We examined the anticancer effects of a novel sirtuin inhibitor, MHY2256, on HCT116 human colorectal cancer cells to investigate its underlying molecular mechanisms. MHY2256 significantly suppressed the activity of sirtuin 1 and expression levels of sirtuin 1/2 and stimulated acetylation of forkhead box O1, which is a target protein of sirtuin 1. Treatment with MHY2256 inhibited the growth of the HCT116 (TP53 wild-type), HT-29 (TP53 mutant), and DLD-1 (TP53 mutant) human colorectal cancer cell lines. In addition, MHY2256 induced G0/G1 phase arrest of the cell cycle progression, which was accompanied by the reduction of cyclin D1 and cyclin E and the decrease of cyclin-dependent kinase 2, cyclin-dependent kinase 4, cyclin-dependent kinase 6, phosphorylated retinoblastoma protein, and E2F transcription factor 1. Apoptosis induction was shown by DNA fragmentation and increase in late apoptosis, which were detected using flow cytometric analysis. MHY2256 downregulated expression levels of procaspase-8, -9, and -3 and led to subsequent poly(ADP-ribose) polymerase cleavage. MHY2256-induced apoptosis was involved in the activation of caspase-8, -9, and -3 and was prevented by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor. Furthermore, the autophagic effects of MHY2256 were observed as cytoplasmic vacuolation, green fluorescent protein-light-chain 3 punctate dots, accumulation of acidic vesicular organelles, and upregulated expression level of light-chain 3-II. Taken together, these results suggest that MHY2256 could be a potential novel sirtuin inhibitor for the chemoprevention or treatment of colorectal cancer or both.

키워드

SIRT inhibitor; MHY2256; Colorectal cancer cells; Cell cycle arrest; Apoptosis; Autophagy

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