Xanthohumol induces paraptosis of leukemia cells through p38 mitogen activated protein kinase signaling pathway

Abstract

// Xiangquan Mi 1, 2 , Chunming Wang 1 , Chao Sun 3 , Xu Chen 1 , Xiang Huo 1 , Yiming Zhang 2 , Gang Li 2 , Bo Xu 2 , Jun Zhang 4 , Jianxin Xie 4 , Zhenhua Wang 2 , Ji Li 2 1 School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China 2 Center for Mitochondrial and Healthy Aging, College of Life Sciences, Yantai University, Yantai, Shandong 264005, P.R. China 3 Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, P.R. China 4 Shihezi University School of Medicine, Shihezi, Xinjiang 832000, P.R. China Correspondence to: Ji Li, email: lijimelissafang@yahoo.com Keywords: xanthohumol, paraptosis, p38-MAPK, cytoplasmic vacuolation, ER stress Received: November 22, 2016      Accepted: March 06, 2017      Published: March 14, 2017 ABSTRACT Xanthohumol as a natural polyphenol demonstrates an anticancer activity, but its underlying mechanism remains unclear. In this study, we showed that xanthohumol (XN) induces paraptosis of leukemia cells. The paraptosis is one cell death which is characterized by dilation of the endoplasmic reticulum and/or mitochondria. The results demonstrated that XN treatment significantly inhibited cell proliferation and triggered extensive cytoplasmic vacuolation of HL-60 leukemia cells, but it did not cause the cleavage of caspase-3 protein or apoptosis. In contrast, XN treatment resulted in LC3-II accumulation through blocking of autophagosome maturation. Interestingly, the induction of cytoplasmic vacuolization by XN is not associated with autophagy modulated by XN, therefore, XN-induced cell death of HL-60 leukemia cells is not the classical apoptotic cell death. Intriguingly, XN treatment triggered the dilatation of endoplasma reticulum (ER) and induced ER stress by upregulating C/EBP homologous protein and unfolded protein response regulator Grp78/Bip. Furthermore, XN treatment triggered p38 mitogen activated protein kinase and its specific inhibitor inhibited the paraptosis of HL-60 leukemia cells by XN. In conclusion, we for the first time demonstrated that XN treatment can induce paraptosis of leukemia cells through activation of p38 MAPK signaling.