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

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

doi:10.18632/oncotarget.4422

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.

Highlights

Folic acid is an essential micronutrient and a critical coenzymes for the de novo synthesis of purine and thymidylate nucleotides and methylation and demethylation of homocysteine/methionine [1,2,3]
Using siRNA and Epigallocatechin gallate (EGCG), we found that glucose-regulated protein 78 (GRP78) and Survivin cooperatively conferred multi-drug resistance (MDR) by decreasing folate deficiency (FD)-induced reactive oxygen species (ROS) generation
As judged by the viability data, except for Hep G2 cells, all three other hepatocellular carcinoma (HCC) cell types cultivated under FD condition could unilaterally transform themselves into MDR phenotype

Summary

Introduction

Folic acid (folate; vitamin B9) is an essential micronutrient and a critical coenzymes for the de novo synthesis of purine and thymidylate nucleotides and methylation and demethylation of homocysteine/methionine [1,2,3]. Most HCC patients are prone to folate deficiency [13,14,15]. Kuo et al [15] reported that approximately 60% of HCC patients were deficient in folate and established that folate levels decreased drastically as HCC stage progressed. They suggested that low blood folate status could be a risk factor for tumor progression. These studies established that folate deprivation is a risk factor for HCC

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Conclusion