The N-terminal polypeptide derived from viral macrophage inflammatory protein II reverses breast cancer epithelial-to-mesenchymal transition via a PDGFRα-dependent mechanism
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Qing-Ling Yang1,2,*, Ling-Yu Zhang3,*, Hai-Feng Wang3,*, Yu Li3, Yue-Yue Wang3, Tian-Tian Chen3, Meng-Fen Dai3, Hai-Hua Wu3, Su-Lian Chen2, Wen-Rui Wang4, Qiong Wu5, Chang-Jie Chen2 and Cong-Zhao Zhou1
1Hefei National Laboratory for Physical Sciences at Microscale and the Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 233030, China
2Department of Biochemistry and Molecular Biology, Bengbu Medical College, Bengbu, Anhui 233030, China
3Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
4Department of Biotechnology, Bengbu Medical College, Bengbu, Anhui 233030, China
5Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China
*These authors have contributed equally to this work
Chang-Jie Chen, email: [email protected]
Cong-Zhao Zhou, email: [email protected]
Keywords: breast cancer, paclitaxel, epithelial-mesenchymal transition, viral macrophage inflammatory protein II, PDGFRα
Received: June 30, 2016 Accepted: March 01, 2017 Published: March 21, 2017
NT21MP, a 21-residue peptide derived from the viral macrophage inflammatory protein II, competed effectively with the natural ligand of CXC chemokine receptor 4 (CXCR4), stromal cell-derived factor 1-alpha, to induce apoptosis and inhibit growth in breast cancer. Its role in tumor epithelial-to-mesenchymal transition (EMT) regulation remains unknown. In this study, we evaluated the reversal of EMT upon NT21MP treatment and examined its role in the inhibition of EMT in breast cancer. The parental cells of breast cancer (SKBR-3 and MCF-7) and paclitaxel-resistant (SKBR-3 PR and MCF-7 PR) cells were studied in vitro and in combined immunodeficient mice. The mice injected with SKBR-3 PR cells were treated with NT21MP through the tail vein or intraperitoneally with paclitaxel or saline. Sections from tumors were evaluated for tumor weight and EMT markers based on Western blot. In vitro, the effects of NT21MP, CXCR4 and PDGFRα on tumor EMT were assessed by relative quantitative real-time reverse transcription–polymerase chain reaction, western blot and biological activity in breast cancer cell lines expressing high or low levels of CXCR4. Our results illustrated that NT21MP could reverse the phenotype of EMT in paclitaxel-resistant cells. Furthermore, we found that NT21MP governed PR-mediated EMT partly due to controlling platelet-derived growth factors A and B (PDGFA and PDGFB) and their receptor (PDGFRα). More importantly, NT21MP down-regulated AKT and ERK1/2 activity, which were activated by PDGFRα, and eventually reversed the EMT. Together, these results indicated that CXCR4 overexpression drives acquired paclitaxel resistance, partly by activating the PDGFA and PDGFB/PDGFRα autocrine signaling loops that activate AKT and ERK1/2. Inhibition of the oncogenic EMT process by targeting CXCR4/PDGFRα-mediated pathways using NT21MP may provide a novel therapeutic approach towards breast cancer.
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