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Ailanthone Inhibits Proliferation, Migration and Invasion of Osteosarcoma Cells by Downregulating the Serine
Yawen Zhang1, Runze Gong1, Yong Liu2
1Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
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.
Insights
Ailanthone (AIL) suppresses osteosarcoma (OS) growth by targeting the serine biosynthetic pathway (SSP). This natural compound shows potential as a novel therapeutic strategy for this common bone cancer.
Area of Science:
- Oncology
- Metabolic pathways
- Pharmacology
Background:
- Osteosarcoma (OS) is the most common primary bone cancer, with chemoresistance hindering effective treatment.
- Metabolic reprogramming is a key feature of cancer, offering potential therapeutic targets.
- Ailanthone (AIL), derived from Ailanthus altissima, is investigated for its anti-cancer properties.
Purpose of the Study:
- To investigate the anti-cancer effects of Ailanthone (AIL) on osteosarcoma (OS).
- To elucidate the molecular mechanisms underlying AIL's action, focusing on metabolic reprogramming.
Main Methods:
- In vitro and in vivo studies of OS cell growth, migration, and invasion.
- Transcriptomics, proteomics, and metabolomics analyses to identify altered pathways.
- Quantitative real-time PCR (qRT-PCR) and Western blot assays to validate gene and protein expression.
- Functional rescue experiments involving PHGDH overexpression and serine supplementation.
Main Results:
- AIL significantly inhibited OS cell growth, migration, and invasion, while inducing cell cycle arrest and apoptosis.
- AIL treatment led to widespread metabolic changes in OS cells, notably downregulating the serine biosynthetic pathway (SSP).
- Expression of key SSP genes (PHGDH, PSAT1, PSPH) was dose-dependently reduced by AIL at both transcript and protein levels.
- Downstream SSP pathways, including one-carbon metabolism and nucleotide synthesis, were also suppressed.
- PHGDH overexpression, but not exogenous serine, partially reversed AIL's effects, implicating SSP in AIL's mechanism.
Conclusions:
- Ailanthone (AIL) exhibits significant anti-tumor activity against osteosarcoma (OS).
- AIL exerts its effects, at least in part, by suppressing the serine biosynthetic pathway (SSP) and associated metabolic reprogramming.
- AIL represents a promising candidate for developing novel therapeutic strategies for osteosarcoma.
