PRECLINICAL REPORTS3-Bromopyruvate enhances TRAIL-induced apoptosis in human nasopharyngeal carcinoma cells through CHOP-dependent upregulation of TRAIL-R2Can, Zhoua,*; Lele, Songb,*; Zhirui, Zhanga; Qiong, Pana; Yuzhong, Chenc; Lingling, Liud; Surong, Zhaoa; Yiming, Suna; Pei, Zhanga; Chenchen, Jiange; Liu, HaoaAuthor Information aFaculty of Pharmacy, Bengbu Medical College bDepartment of Pharmacy cDepartment of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College dDepartment of Pharmacy, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China eSchool of Medicine and Public Health, Faculty of Health, Newcastle University, Newcastle, New South Wales, Australia * Can Zhou and Lele Song contributed equally to the writing of this article. Correspondence to Jiang Chenchen, School of Medicine and Public Health, Faculty of Health, University of Newcastle, Newcastle, NSW 999029, Australia Tel: +86 124 921 7233; fax: +86 552 317 5228; e-mail: email@example.com. Correspondence to Hao Liu, PhD, Faculty of Pharmacy, Bengbu Medical College, Bengbu 233000, Anhui, People’s Republic of China Tel: +86 552 317 5230; fax: +86 552 317 5228; e-mail: firstname.lastname@example.org Received October 29, 2016 Accepted March 7, 2017 Anti-Cancer Drugs: August 2017 - Volume 28 - Issue 7 - p 739-749 doi: 10.1097/CAD.0000000000000502 Buy Metrics Abstract Past reports have shown that the sensitivity of cancer cells to TRAIL-induced apoptosis is related to their expression of TRAIL-death receptors on the cell surface. However, the level of TRAIL-death receptors expression on cancer cells is always low. Our previous research showed that nasopharyngeal carcinoma (NPC) cells have a poor sensitivity to low doses of TRAIL. Here, we evaluated combined treatment with the energy inhibitor 3-bromopyruvate (3BP) and TRAIL as a method to produce an increased apoptotic response in NPC cells. The results showed that 3BP and TRAIL together produced higher cytotoxicity and increased TRAIL-R2 expression in NPC cells compared with the effects of either 3BP or TRAIL alone. These findings led us to hypothesize that 3BP may sensitize NPC cells to TRAIL. 3BP is a metabolic blocker that inhibits hexokinase II activity, suppresses ATP production, and induces endoplasmic reticulum (ER) stress. Our results showed that 3BP also activated AMP-activated protein kinase, which we found to play an important role in the induction of ER stress by 3BP. Furthermore, the induction of TRAIL-R2 expression and the sensitization of the NPC cells to TRAIL by 3BP were reduced when we inhibited the expression of CHOP. Taken together, our results showed that a low dose of 3BP sensitized NPC cells to TRAIL-induced apoptosis by the upregulation of CHOP, which was mediated by the activation of AMP-activated protein kinase and ER stress. The results showed that 3BP is a promising candidate agent for enhancing the therapeutic response to TRAIL in NPC. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.