Journal
ONCOTARGET
Volume 6, Issue 6, Pages 3963-3976Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2894
Keywords
Morphine; cancer stem cell; chemoresistance; nalmefene; epithelial to mesenchymal transition
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Funding
- National Basic Research Program of China (973 Program) [2012CB967000]
- National Natural Science Fund of China [81273923, 81130040]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT13049]
- Liaoning NSF [2014029102]
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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/beta-catenin signaling to induce epithelial to mesenchymal transition and promotes metastasis. Moreover, morphine decreases the sensitivity of traditional anticancer 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.
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