Glucose Deprivation Induces Chemoresistance In Colorectal Cancer Cells By Increasing ATF4 Expression

Purpose Chemoresistance is a major obstacle in the treatment of solid tumors. Recent data showed that tumor microenvironment is an important determinant of malignant progression and chemoresistance. Changes in the tumor microenvironment, such as hypoxia and glucose deprivation(GD), can prompt tumor progression and drug resistance. However, little was known about the role of GD in the chemoresistance of colorectal cancer(CRC) cells. We therefore investigated the role and mechanism of GD in CRC drug resistance.Methods Chemosensitivity and apoptosis were measured under the GD condition. Inhibition of activating transcription factor 4(ATF4) using sh RNA in CRC cells under the GD condition and in ATF4-overexpressed CRC cells were performed to identify the role of ATF4 in the GD induced chemoresistance. q RT-PCR and Western blotting were used to the m RNA and protein expression of MDR1.Results In this study, we observed that 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. Meanwhile, we demonstrated that depletion of ATF4 in CRC cells under the GD condition can induce apoptosis and drug re-sensitization. Similarly, inhibition of ATF4 in the ATF4-overexpressed 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, and ATF4 is an attractive therapeutic target to combat therapeutic resistance in CRC cells.