Hu YL, Yin Y, Liu HY, Feng YY, Bian ZH, Zhou LY, Zhang JW, Fei BJ, Wang YG, Huang ZH. Glucose deprivation induces chemoresistance in colorectal cancer cells by increasing ATF4 expression. World J Gastroenterol 2016; 22(27): 6235-6245 [PMID: 27468213 DOI: 10.3748/wjg.v22.i27.6235]
Corresponding Author of This Article
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
Research Domain of This Article
Oncology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
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/
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Data sharing statement: No additional unpublished data are available.
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.
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.
