1. Glucose deprivation induces chemoresistance in colorectal cancer cells by increasing ATF4 expression.
- Author
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Hu YL, Yin Y, Liu HY, Feng YY, Bian ZH, Zhou LY, Zhang JW, Fei BJ, Wang YG, and Huang ZH
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Activating Transcription Factor 4 metabolism, Apoptosis genetics, Blotting, Western, Cell Line, Tumor, Endoplasmic Reticulum Chaperone BiP, Fluorouracil administration & dosage, Gene Knockdown Techniques, Glucose metabolism, HCT116 Cells, Heat-Shock Proteins genetics, Heat-Shock Proteins metabolism, Humans, Organoplatinum Compounds administration & dosage, Oxaliplatin, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, eIF-2 Kinase genetics, eIF-2 Kinase metabolism, Activating Transcription Factor 4 genetics, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Proliferation drug effects, Colorectal Neoplasms metabolism, Drug Resistance, Neoplasm genetics, Glucose deficiency, Tumor Microenvironment
- 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.
- Published
- 2016
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