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Xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating endoplasmic reticulum stress-dependent CHOP pathway

Authors: Yu-yang Ma1,2, Ze-min Di1,2, Qing Cao1,2, Wen-shuang Xu1,2, Si-xing Bi1,2,3, Ji-shuang Yu1,2, Yu-jun Shen1,2, Yong-qiang Yu3, Yu-xian Shen1,2, Li-jie Feng1,2
1 School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
2 Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
3 The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
Correspondence to: Yu-xian Shen: shenyx@ahmu.edu.cn,
DOI: 10.1038/s41401-019-0318-5
Received: 23 April 2019
Accepted: 9 October 2019
Advance online: 7 November 2019

Abstract

Xanthatin is a natural sesquiterpene lactone purified from Xanthium strumarium L., which has shown prominent antitumor activity against a variety of cancer cells. In the current study, we investigated the effect of xanthatin on the growth of glioma cells in vitro and in vivo, and elucidated the underlying mechanisms. In both rat glioma C6 and human glioma U251 cell lines, xanthatin (1–15 μM) dose-dependently inhibited cell viability without apparent effect on the cell cycle. Furthermore, xanthatin treatment dose-dependently induced glioma cell apoptosis. In nude mice bearing C6 glioma tumor xenografts, administration of xanthatin (10, 20, 40 mg·kg−1·d−1, ip, for 2 weeks) dose-dependently inhibited the tumor growth, but did not affect the body weight. More importantly, xanthatin treatment markedly increased the expression levels of the endoplasmic reticulum (ER) stress-related markers in both the glioma cell lines as well as in C6 xenografts, including glucose-regulated protein 78, C/EBP-homologous protein (CHOP), activating factor 4, activating transcription factor 6, spliced X-box binding protein-1, phosphorylated protein kinase R-like endoplasmic reticulum kinase, and phosphorylated eukaryotic initiation factor 2a. Pretreatment of C6 glioma cells with the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 7 mM) or knockdown of CHOP using small interfering RNA significantly attenuated xanthatin-induced cell apoptosis and increase of proapoptotic caspase-3. These results demonstrate that xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating the ER stress-related unfolded protein response pathway involving CHOP induction. Xanthatin may serve as a promising agent in the treatment of human glioma.
Keywords: glioma; xanthatin; apoptosis; endoplasmic reticulum stress; CHOP; 4-phenylbutyric acid; rat glioma C6 cell line; human glioma U251 cell line

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