title: Glucose deprivation induces chemoresistance in colorectal cancer cells by increasing ATF4 expression.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  These data indicate that GD promotes chemoresistance in CRC cells through up-regulating ATF4 expression.
authors.affiliation: 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.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yin
authors.affiliation: 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.
authors.forename: He-Yong
authors.initials: HY
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yu-Yang
authors.initials: YY
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Ze-Hua
authors.initials: ZH
authors.lastname: Bian
authors.affiliation: 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.
authors.forename: Le-Yuan
authors.initials: LY
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Ji-Wei
authors.initials: JW
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Bo-Jian
authors.initials: BJ
authors.lastname: Fei
authors.affiliation: 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.
authors.forename: Yu-Gang
authors.initials: YG
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Huang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000235:genetics* / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005472:Fluorouracil / Q000008:administration & dosage; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000172:deficiency* / Q000378:metabolism; D045325:HCT116 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D051701:Activating Transcription Factor 4; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; D005947:Glucose; D005472:Fluorouracil
keywords: 5-Fluorouracil; ATF4; Chemoresistance; Glucose deprivation; Oxaliplatin