Int J Biol Sci 2020; 16(11):1901-1916. doi:10.7150/ijbs.44343

Research Paper

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

In Hwan Tae1, Ji Yeon Son1, Su Hyun Lee1, Mi-Young Ahn2, Kyungsil Yoon3, Sungpil Yoon1, Hyung Ryong Moon4,✉, Hyung Sik Kim1,✉

1. School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Suwon 16419, Republic of Korea.
2. Major in Pharmaceutical Engineering, Division of Bio-industry, College of Medical and Life Sciences, Silla University, Busan 46958, Republic of Korea.
3. Comparative Biomedicine Research Branch, Division of Translational Science, National Cancer Center, 323 Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
4. College of Pharmacy, Pusan National University, Busandaehak-ro 63, Geumjeong-gu, Busan 46241, Republic of Korea.

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Citation:
Tae IH, Son JY, Lee SH, Ahn MY, Yoon K, Yoon S, Moon HR, Kim HS. A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells. Int J Biol Sci 2020; 16(11):1901-1916. doi:10.7150/ijbs.44343. Available from http://www.ijbs.com/v16p1901.htm

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Abstract

Ovarian cancer is a common gynecological cancer that is found worldwide. Class III histone deacetylase (HDAC) inhibitors, a new class of anticancer agents, induce autophagy in various human cancer cells. The aim of the present study was to investigate the antitumor activity of MHY2245, a new synthetic SIRT inhibitor, on human ovarian cancer cells. We found that MHY2245 exhibited potent cytotoxicity to SKOV3 cells in a time- and concentration-dependent manner. The cytotoxicity of MHY2245 (IC50=0.32 µM) was higher than that of doxorubicin (DOX, IC50=1.38µM) against SKOV3 cells. MHY2245 significantly inhibited SIRT1 enzyme activity, reduced the expression of SIRT1, increased cell cycle arrest at G2/M phase, and induced apoptotic cell death in SKOV3 cells via expression of cytochrome c, cleaved-PARP, cleaved caspase-3, and Bax. This might be associated with blocking of the pyruvate kinase M2 (PKM2)/mTOR pathway. MHY2245 also inhibited tumor growth and reduced tumor size when SKOV3 cells were transplanted into nude mice. Our results indicate that MHY2245 exerts antitumor activity against ovarian cancer cells by blocking the PKM2/mTOR pathway. We suggest that MHY2245 is a promising anticancer agent that disrupts ovarian cancer cell metabolism.

Keywords: Sirtuin, MHY2245, autophagy, PKM2/mTOR, ovarian cancer