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Pleiotrophin promotes chemoresistance to doxorubicin in osteosarcoma by upregulating P-glycoprotein.

ABSTRACT: 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.

SUBMITTER: Wu D

PROVIDER: S-EPMC5609967 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Osteosarcoma is the most common type of pediatric bone tumor. Despite great advances in chemotherapy during the past decades, the survival rates of osteosarcoma patients remain unsatisfactory. Drug resistance is one of the main reasons, leading to treatment failure and poor prognosis. Previous reports correlated expression of cluster of differentiation 44 (CD44) with drug resistance and poor survival of osteosarcoma patients, however the underlying mechanisms are poorly defined. Here, we investigated the role of CD44 in the regulation of drug chemoresistance, using osteosarcoma cells isolated from mice carrying a mutation of the tumor suppressor neurofibromatosis type 2 (Nf2) gene. CD44 expression was knocked-down in the cells using CRISPR/Cas9 approach. Subsequently, CD44 isoforms and mutants were re-introduced to investigate CD44-dependent processes. Sensitivity to doxorubicin was analyzed in the osteosarcoma cells with modified CD44 expression by immunoblot, colony formation- and WST-1 assay. To dissect the molecular alterations induced by deletion of Cd44, RNA sequencing was performed on Cd44-positive and Cd44-negative primary osteosarcoma tissues isolated from Nf2-mutant mice. Subsequently, expression of candidate genes was evaluated by quantitative reverse transcription PCR (qRT-PCR). Our results indicate that CD44 increases the resistance of osteosarcoma cells to doxorubicin by up-regulating the levels of multidrug resistance (MDR) 1 protein expression, and suggest the role of proteolytically released CD44 intracellular domain, and hyaluronan interactions in this process. Moreover, high throughput sequencing analysis identified differential regulation of several apoptosis-related genes in Cd44-positive and -negative primary osteosarcomas, including p53 apoptosis effector related to PMP-22 (Perp). Deletion of Cd44 in osteosarcoma cells led to doxorubicin-dependent p53 activation and a profound increase in Perp mRNA expression. Overall, our results suggest that CD44 might be an important regulator of drug resistance and suggest that targeting CD44 can sensitize osteosarcoma to standard chemotherapy.

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Pleiotrophin promotes chemoresistance to doxorubicin in osteosarcoma by upregulating P-glycoprotein.

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