Folate deficiency-triggered redox pathways confer drug resistance in hepatocellular carcinoma
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Chun-Te Ho1,*, Hung-Sheng Shang2,*, Jin-Biou Chang2,*, Jun-Jen Liu3, Tsan-Zon Liu4
1Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
2Department of Pathology, National Defense Medical Center, Division of Clinical Pathology, Tri-Service General Hospital, Taipei, Taiwan
3School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan
4Translational Research Laboratory, Cancer Center, Taipei Medical University and Hospital, Taipei, Taiwan
*These authors have contributed equally to this work
Tsan-Zon Liu, e-mail: [email protected]
Jun-Jen Liu, e-mail: [email protected]
Keywords: chemotherapy, folate, GRP78, multi-drug resistance, hepatoma
Received: February 22, 2015 Accepted: June 17, 2015 Published: June 27, 2015
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.
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