Pleiotrophin promotes chemoresistance to doxorubicin in osteosarcoma by upregulating P-glycoprotein
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Dapeng Wu1,*, Liguo Liu2,*, Xuebing Yan3,*, Chunyan Wang1, Yaling Wang1, Kun Han1, Shuchen Lin1, Zhihua Gan1 and Daliu Min1
1Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
2Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
3Department of General Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
*These authors have contributed equally to this work
Daliu Min, email: [email protected]
Keywords: PTN, osteosarcoma, chemoresistance, doxorubicin, β-catenin
Received: December 02, 2016 Accepted: June 10, 2017 Published: July 10, 2017
Chemoresistance is a major hindrance to successful treatment of osteosarcoma (OS). Pleiotrophin (PTN), a neurotrophic growth factor, has been linked to the malignant characteristics of various cancer types. We retrospectively examined the correlation between PTN expression and chemoresistance in OS in a cohort of 133 OS patients. Immunohistochemistry revealed that PTN expression correlated with the necrosis rate and local OS recurrence. In a prognostic analysis, high PTN expression was associated with poor overall and disease-free survival, and was an independent adverse prognostic factor for disease-free survival. In doxorubicin-treated OS cells, PTN knockdown enhanced cellular chemosensitivity, increased the apoptosis rate and inhibited clone formation, while PTN overexpression had the opposite effects. In a xenograft model, PTN knockdown and overexpression respectively enhanced and reduced cellular sensitivity to doxorubicin. PTN upregulated anaplastic lymphoma kinase (ALK), p-Glycogen Synthase Kinase (GSK)3β, β-catenin and multidrug resistance protein 1/P-glycoprotein (MDR1/P-gp). In rescue assays with the β-catenin inhibitor XAV939 and the MDR1/P-gp inhibitor verapamil, PTN promoted chemoresistance to doxorubicin in OS cells by activating ALK/GSK3β/β-catenin signaling, thereby upregulating MDR1/P-gp. Therefore, PTN could be used as a biomarker predicting chemotherapeutic responses, and downregulating PTN could be a promising therapeutic strategy to prevent chemoresistance in OS patients.
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