JNK suppression of chemotherapeutic agents-induced ROS confers chemoresistance on pancreatic cancer stem cells

Abstract

// Shuhei Suzuki 1, 2, 3, * , Masashi Okada 1, * , Keita Shibuya 1, 4, 5 , Manabu Seino 1, 6 , Atsushi Sato 7 , Hiroyuki Takeda 1, 2 , Shizuka Seino 1, 4, 5, 8 , Takashi Yoshioka 2 , Chifumi Kitanaka 1, 4, 5, 8 1 Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan 2 Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata 990-9585, Japan 3 Department of Regional Cancer Network, Yamagata University School of Medicine, Yamagata 990-9585, Japan 4 Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata 990-9585, Japan 5 Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo 102-8471, Japan 6 Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata 990-9585, Japan 7 Department of Neurosurgery, Yamagata University School of Medicine, Yamagata 990-9585, Japan 8 Research Institute for Promotion of Medical Sciences, Yamagata University School of Medicine, Yamagata 990-9585, Japan * These authors contributed equally to this work Correspondence to: Chifumi Kitanaka, e-mail: ckitanak@med.id.yamagata-u.ac.jp Keywords: cancer initiating cells, chemotherapy, combination therapy, c-Jun N-terminal kinase Received: September 01, 2014      Accepted: November 03, 2014      Published: November 19, 2014 ABSTRACT Chemoresistance associated with cancer stem cells (CSCs), which is now being held responsible for the pervasive therapy resistance of pancreatic cancer, poses a major challenge to the successful management of this devastating malignancy. However, the molecular mechanism underlying the marked chemoresistance of pancreatic CSCs remains largely unknown. Here we show that JNK, which is upregulated in pancreatic CSCs and contributes to their maintenance, is critically involved in the resistance of pancreatic CSCs to 5-fluorouracil (5-FU) and gemcitabine (GEM). We found that JNK inhibition effectively sensitizes otherwise chemoresistant pancreatic CSCs to 5-FU and GEM. Significantly, JNK inhibition promoted 5-FU- and GEM-induced increase in intracellular reactive oxygen species (ROS), and scavenging intracellular ROS by use of N-acetylcysteine impaired JNK inhibition-mediated promotion of the cytotoxicity of 5-FU and GEM. Our findings thus suggest that JNK may contribute to the chemoresistance of pancreatic CSCs through prevention of chemotherapeutic agents-induced increase in intracellular ROS. Our findings also suggest that JNK inhibition combined with 5-FU- and/or GEM-based regimens may be a rational therapeutic approach to effectively eliminate pancreatic CSCs.