Int J Biol Sci 2019; 15(8):1637-1653. doi:10.7150/ijbs.33790

Research Paper

PERK/eIF-2α/CHOP Pathway Dependent ROS Generation Mediates Butein-induced Non-small-cell Lung Cancer Apoptosis and G2/M Phase Arrest

Shouyin Di1*, Chongxi Fan2*, Zhiqiang Ma1*, Mingyang Li3, Kai Guo1, Donghui Han4, Xiaofei Li1✉*, Deguang Mu5✉*, Xiaolong Yan1✉*

1. Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
2. Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
3. Department of Pathology, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
4. Department of Urology, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
5. Department of Respiratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou Medicine College, 158 Shangtang Road, Hangzhou 310014, China
*These authors contributed equally to this work.

Abstract

Butein, a member of the chalcone family, is a potent anticarcinogen against multiple cancers, but its specific anti-NSCLC mechanism remains unknown. The present study examined the effects of butein treatment on NSCLC cell lines and NSCLC xenografts. Butein markedly decreased NSCLC cell viability; inhibited cell adhesion, migration, invasion, and colony forming ability; and induced cell apoptosis and G2/M phase arrest in NSCLC cells. Moreover, butein significantly inhibited PC-9 xenograft growth. Both in vivo and in vitro studies verified that butein exerted anti-NSCLC effect through activating endoplasmic reticulum (ER) stress-dependent reactive oxygen species (ROS) generation. These pro-apoptotic effects were reversed by the use of 4- phenylbutyric acid (4-PBA), CHOP siRNA, N-acetyl-L-cysteine (NAC) and Z-VAD-FMK (z-VAD) in vitro. Moreover, inhibition of ER stress markedly reduced ROS generation. In addition, in vivo studies further confirmed that inhibition of ER stress or oxidative stress partially abolished the butein-induced inhibition of tumor growth. Therefore, butein is a potential therapeutic agent for NSCLC, and its anticarcinogenic action might be mediated by ER stress-dependent ROS generation and the apoptosis pathway.

Keywords: Butein, Non-small-cell lung cancer, Endoplasmic reticulum stress, Oxidative stress, Apoptosis

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How to cite this article:
Di S, Fan C, Ma Z, Li M, Guo K, Han D, Li X, Mu D, Yan X. PERK/eIF-2α/CHOP Pathway Dependent ROS Generation Mediates Butein-induced Non-small-cell Lung Cancer Apoptosis and G2/M Phase Arrest. Int J Biol Sci 2019; 15(8):1637-1653. doi:10.7150/ijbs.33790. Available from http://www.ijbs.com/v15p1637.htm