Morphine promotes cancer stem cell properties, contributing to chemoresistance in breast cancer

// Dong-Ge Niu 1, 2, 3, * , Fei Peng 1, 2, * , Wei Zhang 1, 2 , Zhong Guan 4 , Hai-Dong Zhao 5 , Jing-Lin Li 1, 2, 3 , Kai-Li Wang 1, 2, 5 , Ting-Ting Li 1, 2 , Yan Zhang 1, 2 , Fei-Meng Zheng 1, 2 , Fan Xu 1, 2, 6 , Qian-Ni Han 1, 2, 3 , Peng Gao 3 , Qing-Ping Wen 3 , Quentin Liu 1, 2 1 Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China 2 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China 3 Department of Anesthesia, The First Affiliated Hospital, Dalian Medical University, Dalian 116044, China 4 Department of Otorhinolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China 5 Department of Breast Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China 6 Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China * These authors have contributed equally to this work Correspondence to: Quentin Liu, e-mail: liuq9@mail.sysu.edu.cn Qing-Ping Wen, e-mail: wqp.89@163.com Keywords: Morphine, cancer stem cell, chemoresistance, nalmefene, epithelial to mesenchymal transition Received: September 20, 2014      Accepted: December 11, 2014      Published: February 20, 2015 ABSTRACT Morphine is an opioid analgesic drug commonly used for pain relief in cancer patients. Here, we report that morphine enhances the mammosphere forming capacity and increases the expression of stemness-related transcription factors Oct4, Sox2 and Nanog. Treatment with morphine leads to enrichment of a side population fraction in MCF-7 cells and the CD44 + /CD24 −/low population in BT549 cells. Consistently, morphine activates Wnt/β-catenin signaling to induce epithelial to mesenchymal transition and promotes metastasis. Moreover, morphine decreases the sensitivity of traditional anti-cancer drugs in breast cancer cells. Nalmefene, an antagonist of morphine, reverses morphine-induced cancer stem cell properties and chemoresistance in breast cancer. In addition, nalmefene abolishes morphine enhancing tumorigenesis in a NOD/SCID mouse model. In conclusion, our findings demonstrate that morphine contributes to chemoresistance via expanding the population of cancer stem cells and promotes tumor growth, thereby revealing a novel role of morphine and providing some new guides in clinical use of morphine.