The flavonoid TL-2-8 induces cell death and immature mitophagy in breast cancer cells via abrogating the function of the AHA1/Hsp90 complex

• 来源期刊: 中国药理学报（英文版）
• 关键词: flavonoids quercetin breast cancer heat shock proteins AHA1 inhibitor PLK1 mitophagy
• 年，卷（期）: 2017,（10）
• 页码范围: 1381-1393
• 页数: 13页
• 语种: 英文
• DOI: 10.1038/aps.2017.9

摘要

The flavonoid quercetin exhibits significant anticancer activities with few side effects.In the current study,we characterized TL-2-8,a quercetin derivative,as a novel anticancer agent in vitro and in vivo.Cell proliferation and viability were assessed using Cell Counting Kit-8 and CellTiter-Blue assay,respectively.Ceil death was examined using PI staining or a TUNEL assay.Mitophagy was determined by measuring autophagic flux and by confocal imaging.Protein expression was examined by Western blotting.We found that TL-2-8 selectively inhibited the proliferation and decreased the viability of various cancer cells (the anti-proliferation IC50 values in MDA-MB-231,MDA-MB-468 and MCF-7 breast cancer cells at 72 h were 8.28,8.56,and 9.58 μmol/L,respectively),and it displayed only slight cytotoxicity against normal MCF-1OA and HEK-293 cells.In MDA-MB-231 and MDA-MB-468 breast cancer cells,TL-2-8 treatment induced the degradation of multiple Hsp90 client proteins without inducing Hsp70.TL-2-8 (3,6,12 μmol/L) dose-dependently inhibited the expression of AHA1,an activator of Hsp90 ATPase,and decreased Hsp90-AHA1 complex formation,leading to decreased Hsp90 chaperone function and reduced polo-like kinase 1 (PLK1) signaling.Consequently,impaired mitophagy was induced via the downregulation of lysosomal-associated membrane protein 2 (LAMP2).The in vivo anticancer effects of TL-2-8 were evaluated in an MDA-MB-231 breast cancer xenograft model,which was treated with TL-2-8 (25,50,100 mg·kg-1·d-1,po).Administration of TL-2-8 resulted in tumor growth inhibition rates of 37.9％,58.9％ and 70.9％,respectively,whereas quercetin treatment (100 mg·kg-1·d-1,po) produced only a lower tumor growth inhibition rate (49.5％).Furthermore,TL-2-8 treatment significantly extended the lifespan of mice bearing MDA-MB-231 breast cancer cell xenografts.Our results demonstrate that TL-2-8 induces significant cell death and immature mitophagy in breast cancer cells in vitro and in vivo via AHA1 abrogation.