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

// Chun-Te Ho 1, * , Hung-Sheng Shang 2, * , Jin-Biou Chang 2, * , Jun-Jen Liu 3 , Tsan-Zon Liu 4 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 * These authors have contributed equally to this work Correspondence to: Tsan-Zon Liu, e-mail: tzliu@tmuh.org.tw Jun-Jen Liu, e-mail: jjliu_96@tmu.edu.tw Keywords: chemotherapy, folate, GRP78, multi-drug resistance, hepatoma Received: February 22, 2015      Accepted: June 17, 2015      Published: June 27, 2015 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.