Ginkgetin induces autophagic cell death through p62/SQSTM1-mediated autolysosome formation and redox setting in non-small cell lung cancer

// Jian-Shu Lou 1, 2 , Wen-Chuan Bi 1, 2 , Gallant K.L. Chan 1, 2 , Yan Jin 1, 2 , Chau-Wing Wong 2 , Zhong-Yu Zhou 2 , Huai-You Wang 1, 2 , Ping Yao 2 , Tina T.X. Dong 1, 2 and Karl W.K. Tsim 1, 2 1 Shenzhen Research Institute, The Hong Kong University of Science and Technology, Shenzhen, China 2 Division of Life Science, Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China Correspondence to: Karl W.K. Tsim, email: botsim@ust.hk Keywords: autophagy, natural compounds, non-small cell lung cancer, p62, mTORC1 Received: July 12, 2017      Accepted: August 27, 2017      Published: October 16, 2017 ABSTRACT Promoting cell death by autophagy could be a novel treatment for cancer. The major player in autophagy, p62, serves as a good therapeutic target. Ginkgetin, a biflavonoid from Ginkgo biloba leaves, exhibited promising anticancer activity in non-small cell lung cancer cell lines, with an IC50 lower than that of cisplatin. This anticancer effect of ginkgetin was illustrated in a xenograft nude mouse model. Ginkgetin induced autophagic cell death in A549 cells, and this effect was markedly reversed by chemical and genetic approaches. Ginkgetin showed potential binding affinity to p62. Upregulation of p62 through chemical and genetic means decreased cell death, lysosome acidification, and autophagosome formation, which consequently disrupted autolysosome formation. In addition, the decreased autophagy induced by p62 overexpression increased Nrf2/ARE activity and the oxygen consumption rate and decreased on formation of reactive oxygen species. These phenomena were exhibited in a reciprocal manner when p62 was knocked down. Thus, p62 may be a potential target in ginkgetin-induced autophagic cell death, and ginkgetin could be developed as a novel anticancer drug.