Abstract
Lobaplatin is a third-generation platinum-based antineoplastic agent and is widely used for osteosarcoma treatment before and after tumor removal. However, treatment failure often results from lobaplatin drug resistance. In our study, we found that SaOS-2 and SOSP-9607 osteosarcoma cells became less sensitive to lobaplatin after treatment with exogenous interleukin (IL)-6. Quantitative proteomic analysis was performed to elucidate the underlying mechanism in SaOS-2 osteosarcoma cells. Cells were divided into a control group (CG), a lobaplatin treatment group (LG), a recombinant human IL-6 (rhIL-6), and a lobaplatin treatment group (rhILG). We performed three biological replicates in each group to compare the differential protein expression between groups using a tandem mass tag (TMT) labeling technology based on liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 1,313 proteins with significant differential expression was identified and quantified. The general characteristics of the significantly enriched proteins were identified by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and protein–protein interaction (PPI) analysis was conducted using IntAct and STRING. In total, 31 proteins were further verified by parallel reaction monitoring (PRM), among which ras GTPase-activating protein-binding protein 1 (G3BP1), fragile X mental retardation syndrome-related protein 1 (hFXR1p), and far upstream element-binding protein 1 (FUBP1) were significantly differentially expressed. Immunohistochemistry results showed that these three proteins are highly expressed in specimens from platinum-resistant osteosarcoma patients, while the proteins are negatively or weakly expressed in specimens from platinum-sensitive osteosarcoma patients. The immunofluorescence staining results were in accord with the immunohistochemistry staining results. siRNA knockdown of FUBP1 showed a strikingly decreased IC50 value for lobaplatin in FUBP1-silenced cells, which verified the role of FUBP1 in the drug susceptibility of osteosarcoma and the potential therapeutic value for increasing the sensitivity to lobaplatin. This is the first proteomic study on a rhIL-6 intervention before lobaplatin treatment in osteosarcoma cells.
Highlights
Osteosarcoma accounts for approximately 44.6% of malignant bone tumors and is the most common primary malignant bone tumor clinically
To assess the potential role of IL-6 in the process of lobaplatin resistance in osteosarcoma cells, 60 ng/mL recombinant human IL-6 (rhIL-6) was applied to SaOS-2 and SOSP-9607 osteosarcoma cells 8 h before lobaplatin treatment
It was demonstrated that the average cell viability of SaOS-2 and SOSP9607 osteosarcoma cells treated with rhIL-6 and with lobaplatin was 73.58% ± 0.021 and 40.86% ± 0.054, while that of SaOS-2 and SOSP-9607 cells treated only with lobaplatin was 52.65% ± 0.0009 and 27.66% ± 0.038, respectively, indicating that SaOS-2 and SOSP-9607 cells pretreated with rhIL-6 exhibit greater resistance to lobaplatin
Summary
Osteosarcoma accounts for approximately 44.6% of malignant bone tumors and is the most common primary malignant bone tumor clinically. Osteosarcoma usually occurs in children and young adolescents and demonstrates poor prognosis [1, 2]. As osteosarcoma is considered less sensitive to radiotherapy, chemotherapy has been the traditional treatment accompanying surgery to improve the survival of tumor-suffering patients [3]. Platinum-based drugs, such as cisplatin, carboplatin, and lobaplatin, are extensively used for osteosarcoma patients [4, 5]. Lobaplatin is a third-generation platinum-based chemotherapy drug with ideal antitumor activity and stability. Osteosarcoma becomes less sensitive to lobaplatin after one or two courses of treatment
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