Ailanthone Inhibits Proliferation, Migration and Invasion of Osteosarcoma Cells by Downregulating the Serine Biosynthetic Pathway

Yawen Zhang,Jinrong Liang,Xin Liu,Runze Gong,Jianjun Zhang,Zan Shen,Lina Tang,Haiyan Hu,Yonggang Wang,Yan Zhou,Xipeng Sun,Yang Yao,Wenxi Yu,Yaling Wang,Yong Liu,Aina He

doi:10.3389/fonc.2022.842406

Abstract

Osteosarcoma (OS) is the most common primary bone sarcoma, chemoresistance becomes an obstacle to its treatment. Metabolic reprogramming is a hallmark of malignancy, targeting the metabolic pathways might provide a reasonable therapeutic strategy for OS. Here we demonstrated that Ailanthone (AIL), a major component of the Chinese medicine Ailanthus altissima, significantly suppressed OS cell growth in vitro and in vivo. Furthermore, AIL dose-dependently inhibited cell migration and invasion, induced cell cycle arrest and apoptosis in OS cells. Combined transcriptomics, proteomics and metabolomics analyses revealed that AIL induced widespread changes in metabolic programs in OS cells, while the serine biosynthetic pathway (SSP) was the most significantly altered pathway. qRT-PCR and Western blot assay confirmed that the transcript and protein levels of the SSP genes (PHGDH, PSAT1 and PSPH) were downregulated dose-dependently by AIL. In addition, we found out that many downstream pathways of the SSP including the one-carbon pool by folate, purine metabolism, pyrimidine metabolism, DNA replication and sphingolipid metabolism were downregulated after AIL treatment. In the revere test, PHGDH overexpression but not exogenous serine supplementation clearly attenuated the effects of AIL on OS cells. Taken together, AIL exerts antitumor effects on OS through mediating metabolic reprogramming, at least in part, by suppressing the SSP. Our findings suggest that AIL could emerge as a potential therapeutic strategy in OS.

Highlights

Osteosarcoma (OS) is the most common primary bone sarcoma, affecting mainly adolescents and young adults [1]
We proposed that AIL inhibited proliferation, migration and invasion of OS cells by downregulating the serine biosynthetic pathway (SSP), further downregulating the pathways of one-carbon pool by folate, purine metabolism, pyrimidine metabolism, DNA replication and sphingolipid metabolism (Figure 7D)
We found that AIL dosedependently inhibited cell proliferation, migration and invasion while inducing G1-S cell cycle arrest and apoptosis in Saos-2 and U-2OS cells

Summary

Introduction

Osteosarcoma (OS) is the most common primary bone sarcoma, affecting mainly adolescents and young adults [1]. The survival of patients with OS has improved considerably with the advent of multi-drug chemotherapy regimen including high-dose methotrexate, doxorubicin, cisplatin and ifosfamide since the late 1970s [2]. Frequent acquisition of drug-resistance becomes an obstacle to its treatment, patients who do not respond to chemotherapy have an overall survival of only 2025% at 5 years [3, 4]. Metabolic reprogramming is a hallmark of malignancy [6]. This metabolic alteration allows tumors to achieve excessive cell growth, proliferation, metastasis potential, as well as drug-resistance [7]. Metabolic shift from oxidative phosphorylation to glycolysis promotes proliferation in osteosarcoma [9] while a higher glycolysis rate of OS cells confers to their cisplatin-resistant property [10]. Given the important role of metabolic reprogramming in OS, targeting the metabolic pathways might provide a new therapeutic strategy for this disease

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Results

Conclusion