Folate deficiency-triggered redox pathways confer drug resistance in hepatocellular carcinoma.
Patients with hepatocellular carcinoma (HCC) are prone to folate deficiency (FD). Here we showed that, in cell line-specific manner, FD caused resistance to FD-induced oxidative stress and multi-drug resistance (MDR). This resistance was due to upregulation of glucose-regulated protein 78 (GRP78) and Survivin. Using siRNA and Epigallocatechin gallate (EGCG), we found that GRP78 and Survivin cooperatively conferred MDR by decreasing FD-induced ROS generation. Our data showed that FD increases GRP78 and Survivin, which serve as ROS inhibitors, causing MDR in HCC. We suggest that folate supplementation may enhance the efficacy of chemotherapy.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Chun-Te
CT
Ho
Department of Pathology, National Defense Medical Center, Division of Clinical Pathology, Tri-Service General Hospital, Taipei, Taiwan.
Hung-Sheng
HS
Shang
Department of Pathology, National Defense Medical Center, Division of Clinical Pathology, Tri-Service General Hospital, Taipei, Taiwan.
Jin-Biou
JB
Chang
School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan.
Jun-Jen
JJ
Liu
Translational Research Laboratory, Cancer Center, Taipei Medical University and Hospital, Taipei, Taiwan.
Tsan-Zon
TZ
Liu
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003470:Culture Media / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D005492:Folic Acid / Q000378:metabolism / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D000077022:Survivin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D003470:Culture Media; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D017382:Reactive Oxygen Species; D000077022:Survivin; D002392:Catechin; D005492:Folic Acid; C045651:epigallocatechin gallate
GRP78; chemotherapy; folate; hepatoma; multi-drug resistance