Folate deficiency-triggered redox pathways confer drug resistance in hepatocellular carcinoma

Chun-Te Ho; Hung-Sheng Shang; Jin-Biou Chang; Jun-Jen Liu; Tsan-Zon Liu

doi:10.18632/oncotarget.4422

Folate deficiency-triggered redox pathways confer drug resistance in hepatocellular carcinoma

Oncotarget. 2015 Sep 22;6(28):26104-18. doi: 10.18632/oncotarget.4422.

Authors

Chun-Te Ho¹, Hung-Sheng Shang², Jin-Biou Chang², Jun-Jen Liu³, Tsan-Zon Liu⁴

Affiliations

¹ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
² Department of Pathology, National Defense Medical Center, Division of Clinical Pathology, Tri-Service General Hospital, Taipei, Taiwan.
³ School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan.
⁴ Translational Research Laboratory, Cancer Center, Taipei Medical University and Hospital, Taipei, Taiwan.

Abstract

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.

Keywords: GRP78; chemotherapy; folate; hepatoma; multi-drug resistance.

MeSH terms

Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Apoptosis / genetics
Blotting, Western
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Catechin / analogs & derivatives
Catechin / pharmacology
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
Culture Media / metabolism
Culture Media / pharmacology
Dose-Response Relationship, Drug
Drug Resistance, Multiple / genetics
Drug Resistance, Neoplasm / genetics
Endoplasmic Reticulum Chaperone BiP
Folic Acid / metabolism
Folic Acid / pharmacology*
Heat-Shock Proteins / genetics
Heat-Shock Proteins / metabolism*
Hep G2 Cells
Humans
Inhibitor of Apoptosis Proteins / genetics
Inhibitor of Apoptosis Proteins / metabolism*
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Oxidation-Reduction
RNA Interference
Reactive Oxygen Species / metabolism
Signal Transduction / drug effects*
Signal Transduction / genetics
Survivin

Substances

Antineoplastic Agents
BIRC5 protein, human
Culture Media
Endoplasmic Reticulum Chaperone BiP
HSPA5 protein, human
Heat-Shock Proteins
Inhibitor of Apoptosis Proteins
Reactive Oxygen Species
Survivin
Catechin
Folic Acid
epigallocatechin gallate