Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 21, 2016; 22(27): 6235-6245
Published online Jul 21, 2016. doi: 10.3748/wjg.v22.i27.6235
Glucose deprivation induces chemoresistance in colorectal cancer cells by increasing ATF4 expression
Ya-Ling Hu, Yuan Yin, He-Yong Liu, Yu-Yang Feng, Ze-Hua Bian, Le-Yuan Zhou, Ji-Wei Zhang, Bo-Jian Fei, Yu-Gang Wang, Zhao-Hui Huang
Ya-Ling Hu, Yuan Yin, He-Yong Liu, Yu-Yang Feng, Ze-Hua Bian, Le-Yuan Zhou, Ji-Wei Zhang, Bo-Jian Fei, Zhao-Hui Huang, Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China
Yu-Gang Wang, Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109, United States
Author contributions: Wang YG and Huang ZH designed the project; Hu YL, Yin Y and Liu HY performed the study; Feng YY and Bian ZH collected the data; Zhou LY, Zhang JW and Fei BJ analyzed the data; Hu YL, Yin Y and Huang ZH wrote the paper.
Supported by National Natural Science Foundation of China, No. 81000867, No. 81272299, No. 81301784 and No. 81301920; Natural Science Foundation of Jiangsu Province, No. BK20150004 and No. BK20151108; the Fundamental Research Funds for the Central Universities, No. NOJUSRP51619B; Medical Key Professionals Program of Jiangsu Province, No. RC2011031; “333” Talents Project of Jiangsu Province, and Hospital Management Center of Wuxi, No. YGZXM1524.
Institutional review board statement: The study does not involve animal subjects.
Conflict-of-interest statement: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Data sharing statement: No additional unpublished data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Zhao-Hui Huang, MD, PhD, Associate Professor, Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, 200 Huihe Road, Wuxi 214062, Jiangsu Province, China. hzhwxsy@126.com
Telephone: +86-510-88682087 Fax: +86-510-88682087
Received: March 23, 2016
Peer-review started: March 24, 2016
First decision: May 12, 2016
Revised: May 25, 2016
Accepted: June 15, 2016
Article in press: June 15, 2016
Published online: July 21, 2016
Processing time: 114 Days and 1.7 Hours
Abstract

AIM: To investigate the role of activating transcription factor 4 (ATF4) in glucose deprivation (GD) induced colorectal cancer (CRC) drug resistance and the mechanism involved.

METHODS: Chemosensitivity and apoptosis were measured under the GD condition. Inhibition of ATF4 using short hairpin RNA in CRC cells under the GD condition and in ATF4-overexpressing CRC cells was performed to identify the role of ATF4 in the GD induced chemoresistance. Quantitative real-time RT-PCR and Western blot were used to detect the mRNA and protein expression of drug resistance gene 1 (MDR1), respectively.

RESULTS: GD protected CRC cells from drug-induced apoptosis (oxaliplatin and 5-fluorouracil) and induced the expression of ATF4, a key gene of the unfolded protein response. Depletion of ATF4 in CRC cells under the GD condition can induce apoptosis and drug re-sensitization. Similarly, inhibition of ATF4 in the ATF4-overexpressing CRC cells reintroduced therapeutic sensitivity and apoptosis. In addition, increased MDR1 expression was observed in GD-treated CRC cells.

CONCLUSION: These data indicate that GD promotes chemoresistance in CRC cells through up-regulating ATF4 expression.

Keywords: Glucose deprivation; ATF4; Oxaliplatin; 5-Fluorouracil; Chemoresistance

Core tip: In this work, we demonstrated that glucose deprivation induces chemoresistance in colorectal cancer (CRC) cells through up-regulating ATF4 expression, and ATF4 is an attractive therapeutic target to combat therapeutic resistance in CRC cells.