Glucose depletion enhances P-glycoprotein expression in hepatoma cells: role of endoplasmic reticulum stress response.
P-Glycoprotein (P-gp) encoded by the MDR gene is one of the main factors in multidrug resistance. Its expression in cancer cells, which compromises cancer outcome, can be enhanced by some stress signals. Energy depletion, frequently observed in malignant cells, was shown to induce chemoresistance and could be one of these signals. To test this hypothesis, we studied the effect of glucose deprivation on P-gp expression in a rat hepatoma cell line (Fao). Incubation of Fao cells with a glucose-free medium enhanced P-gp mRNA and protein expression in a time-dependent manner, up to 400% at 40 h. This effect was associated with a stimulation of [(3)H]vinblastine efflux by P-gp despite impaired glycosylation. It was reproduced by inducers of endoplasmic reticulum stress response, such as 2-deoxyglucose (DG), tunicamycin, and thapsigargin. P-gp mRNA induction by DG was preceded by an increase in activator protein binding activity, c-Jun expression, and phosphorylation. In contrast, nuclear factor-kappaB binding activity was unaffected by DG. The antioxidant N-acetylcysteine partially reversed the increase in P-gp mRNA and protein levels induced by DG, as well as the enhancement of c-Jun phosphorylation and activator protein binding activity. Finally, transient transfection of the cells with a deleted mutant of c-Jun, Tam 67, abolished the DG-induced P-gp mRNA expression and mdr1b promoter activation. In conclusion, glucose deprivation enhances P-gp expression and transport function in liver cancer cells. This effect is mediated by endoplasmic reticulum stress response and involves MDR transcriptional induction through c-Jun activation. These results emphasize the importance of glucose metabolism in chemoresistance.
Ledoux
Severine
S
Institut National de la Santé et de la Recherche Médicale U426, Faculté Xavier Bichat, Institut Fédératif de Recherche 02, 16 rue Henri Huchard, 75018 Paris, France.
Yang
Ruchung
R
Friedlander
Gerard
G
Laouari
Denise
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005947:Glucose / Q000172:deficiency* / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016328:NF-kappa B; D010446:Peptide Fragments; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; C439528:TAM67 peptide; D018808:Transcription Factor AP-1; D003847:Deoxyglucose; D005947:Glucose