Research Paper Volume 12, Issue 23 pp 24208—24218
SRT2183 impairs ovarian cancer by facilitating autophagy
- 1 Department of Gynecology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
- 2 Discovery Department, Elpiscience Biopharma Ltd., Shanghai 201203, China
- 3 Department of Plastic Surgery, Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy, Shenzhen 518055, China
- 4 Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen 518060, China
- 5 Department of General Surgery and Carson International Cancer Research Center, Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy, Shenzhen 518055, China
- 6 Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen 518060, China
- 7 Guangdong Key Laboratory of Regional Immunity and Diseases, Shenzhen University Health Science Center, Shenzhen 518060, China
Received: April 14, 2020 Accepted: September 4, 2020 Published: November 20, 2020
https://doi.org/10.18632/aging.104126How to Cite
Copyright: © 2020 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The 5-year survival rate of ovarian cancer patients is only 47%, and developing novel drugs for ovarian cancer is needed. Herein, we evaluated if and how SRT2183, a sirtuin-1 activator, impairs the ovarian cancer cells. OVCAR-3 and A2780 cells were treated with SRT2183. Cell viability was measured by cell counting kit-8 assay and clonogenic assay. Apoptosis was determined by flow cytometry with Annexin V and propidium iodide. The level of autophagy was evaluated by western blot and immunofluorescence. The activities of AKT/mTOR/70s6k and MAPK signaling pathway were measured by immunoblot. SRT2183 inhibited the growth of ovarian cancer cells, increased the accumulation of BAX, cleaved-caspase 3 and cleaved-PARP, and decreased the level of anti-apoptotic Bcl-2 and Mcl-1. SRT2183 increased the LC3II level, and enhanced the degradation of p62/SQSTM1. SRT2183 increased the formation of GFP-LC3 puncta and induced the maturation of autophagosome. Interestingly, knockdown of autophagy related 5 and 7 significantly impaired the anti-carcinoma activity of SRT2183, implying that SRT2183 impaired the ovarian cancer cells by inducing autophagy. SRT2183 decreased the accumulation of p-Akt, p-mTOR and p-70s6k, and activated the p38 MAPK signaling pathway. This indicated that Akt/mTOR/70s6k and p38 MAPK signaling pathway might be involved in the SRT2183-mediated autophagy and apoptosis.
Abbreviations
AMPK: AMP activated protein kinase; CCK-8: Cell counting kit-8; CQ: Chloroquine; DMEM: Dulbecco’s Modified Eagle’s Medium; FBS: Fetal bovine serum; MAPK: Mitogen-activated protein kinase; p-Akt: Phosphorylation levels of Akt; PI: Propidium iodide; SD: Standard deviation; TEM: Transmission electron microscopy.