Dezocine induces apoptosis in human cervical carcinoma Hela cells via the endoplasmic reticulum stress pathway

Hanlin Wang; Chengyao Chiang; Chenyang Xue; Lu Zhou; Shuaihu Li; Yaqi Zhou; Zhucheng Zhang; Meng Xie; Tian Xiao; Hongyi Hu; Lizhi Zhu; Cheng Long; Yongdong Zou; Ting Wang; Duo Zheng

doi:10.1093/toxres/tfac026

Dezocine induces apoptosis in human cervical carcinoma Hela cells via the endoplasmic reticulum stress pathway

Toxicol Res (Camb). 2022 May 30;11(3):498-510. doi: 10.1093/toxres/tfac026. eCollection 2022 Jun.

Authors

Hanlin Wang¹, Chengyao Chiang², Chenyang Xue¹, Lu Zhou³, Shuaihu Li¹, Yaqi Zhou⁴, Zhucheng Zhang¹, Meng Xie¹, Tian Xiao¹, Hongyi Hu⁴, Lizhi Zhu⁵, Cheng Long⁶, Yongdong Zou¹, Ting Wang⁶, Duo Zheng¹

Affiliations

¹ Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China.
² Central Laboratory, Southern University of Science and Technology Yantian Hospital, Shenzhen 518081, China.
³ Maternal and Child Healthcare Hospital of Shenzhen City, Southern Medical University, Shenzhen 518028, China.
⁴ Department of Otolaryngology, Peking University Shenzhen Hospital, Shenzhen 518036, China.
⁵ Institute of Translation Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
⁶ Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China.

Abstract

Dezocine, a dual agonist and antagonist of the μ-opioid receptor and κ-opioid receptor, is widely used as an analgesic in China. At present, there are few studies on anti-tumor effects of dezocine, most of which are used to treat cancer pain. However, it has recently been reported that dezocine can induce apoptosis of triple negative breast cancer cells. Dezocine may have some anti-tumor activity, but the effect and potential mechanism of dezocine in the treatment of other types of cancer remain to be fully studied. The purpose of the present study was to investigate the effect of dezocine on human Hela cervical carcinoma cells, and to elucidate the underlying molecular mechanisms. We performed CCK-8 assays, clone formation assays, xenograft, flow cytometry analysis, western blot and RNA-seq analysis to evaluate the effects of dezocine on Hela cells. In addition, the role of endoplasmic reticulum (ER) stress in dezocine-induced apoptosis was investigated using qPCR and western blot analysis. Dezocine inhibited Hela cell viability in dose-dependent and time-dependent manners, and notably did not achieve this effect by targeting the opioid receptors. Further mechanistic studies demonstrated that dezocine activated ER stress by upregulating the expression of GRP78, IRE1 and p-JNK, and that dezocine-induced apoptosis was attenuated when the ER stress pathway was blocked. Our results provide a foundation to support the redefinition of dezocine as a novel, adjuvant treatment for patients with cervical cancer, although further research will be required to support its application in clinical practice.

Keywords: ER stress; apoptosis; cervical cancer; dezocine; opioid receptor.