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Sphingosine kinase 1 contributes to doxorubicin resistance and glycolysis in osteosarcoma.

ABSTRACT: Osteosarcoma (OS) is one of the most common and aggressive malignancies in children and adolescents worldwide. Sphingosine kinase 1 (SphK1) has recently been reported to serve a role in OS progression. The present study aimed to investigate the role of SphK1 in the development of chemoresistance and glycolysis in OS cell lines. SphK1 expression levels in OS cell lines (U2OS, MG63 and SaoS2) were analyzed using western blotting and reverse transcription?quantitative PCR (RT?qPCR). A cell survival assay was conducted to determine doxorubicin?resistance in OS cells, and glycolysis was also evaluated. SphK1 expression was increased in the U2OS and SaoS2 cell lines, and both cell lines were more resistant to doxorubicin when compared with the MG63 cell line. SphK1 knockdown or overexpression altered doxorubicin resistance and the viability of OS cell lines. In addition, hypoxia inducible factor?1? (HIF?1?) expression was positively associated with SphK1 expression, and partly mediated SphK1?induced effects on doxorubicin resistance and glycolysis. The present study suggested that SphK1 participated in the development of doxorubicin resistance and contributed to glycolysis in OS cells by regulating HIF?1? expression. However, further studies investigating the application of SphK1 associated therapies for patients with OS are required.

SUBMITTER: Ren X

PROVIDER: S-EPMC7411368 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Sphingosine kinase 1 contributes to doxorubicin resistance and glycolysis in osteosarcoma.

Ren Xiaojun X Su Chunhong C

Molecular medicine reports 20200703 3

Osteosarcoma (OS) is one of the most common and aggressive malignancies in children and adolescents worldwide. Sphingosine kinase 1 (SphK1) has recently been reported to serve a role in OS progression. The present study aimed to investigate the role of SphK1 in the development of chemoresistance and glycolysis in OS cell lines. SphK1 expression levels in OS cell lines (U2OS, MG63 and SaoS2) were analyzed using western blotting and reverse transcription‑quantitative PCR (RT‑qPCR). A cell survival ...[more]

PMID: 32705189

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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.

Dataset Information

Sphingosine kinase 1 contributes to doxorubicin resistance and glycolysis in osteosarcoma.

Publications

Sphingosine kinase 1 contributes to doxorubicin resistance and glycolysis in osteosarcoma.

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