Spermidine Secreted by Apoptotic Cells Enhances Chemotherapy Resistance by Modulating β-Catenin Activity in
Purpose:
Chemoresistance remains a key hurdle in osteosarcoma therapy. This study aims to delineate the role and underlying mechanisms of spermidine (SPD) in osteosarcoma chemoresistance.
Experimental Design:
Using osteosarcoma cell lines and xenografts, we combined flow cytometry, Western blotting, proteomic mass spectrometry, and RNA sequencing to characterize SPD-driven changes in cellular pathways and resistance signatures. We tested whether pharmacologic inhibition of SPD biosynthesis, alone or in combination with standard chemotherapy, improves therapeutic response in vivo.
Results:
Following chemotherapy, either cisplatin (CDP) or doxorubicin (DOX), apoptotic osteosarcoma cells exhibit an upregulation of ornithine decarboxylase 1 and SPD synthase, key enzymes involved in SPD synthesis, resulting in heightened levels of this polyamine. SPD diminishes the therapeutic efficacy of CDP and DOX in osteosarcoma cells, both in vitro and in vivo. Mechanistically, SPD enhances β-catenin activity, which subsequently upregulates genes associated with cancer stemness and ATP-binding cassette transporters, both of which are implicated in drug resistance. Furthermore, pharmacologic inhibition of SPD synthesis using α-difluoromethylornithine markedly increases the chemosensitivity of osteosarcoma cells to CDP and DOX.
Conclusions:
These findings illuminate the critical role of apoptotic cell metabolites in mediating treatment resistance and suggest that targeting SPD may offer a promising therapeutic strategy to augment the effectiveness of chemotherapy in osteosarcoma.
Insights
Spermidine (SPD) increases chemoresistance in osteosarcoma by enhancing cancer stemness and drug efflux. Inhibiting SPD synthesis with DFMO improves chemotherapy effectiveness, offering a new therapeutic strategy for osteosarcoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Chemoresistance is a major challenge in osteosarcoma (OS) treatment.
- Understanding the mechanisms of chemoresistance is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of spermidine (SPD) in mediating chemoresistance in osteosarcoma.
- To elucidate the underlying molecular mechanisms by which SPD affects OS chemoresistance.
Main Methods:
- Utilized osteosarcoma cell lines and xenografts.
- Employed techniques including flow cytometry, Western blotting, proteomic mass spectrometry, and RNA sequencing.
- Assessed the impact of pharmacological SPD synthesis inhibition (DFMO) on chemoresistance in vitro and in vivo.
Main Results:
- Chemotherapy-induced apoptosis in OS cells leads to increased spermidine (SPD) synthesis.
- SPD was found to reduce the efficacy of cisplatin (CDP) and doxorubicin (DOX) in OS cells.
- SPD enhances beta-catenin activity, promoting cancer stemness and ABC transporter expression, contributing to drug resistance.
- Inhibition of SPD synthesis with DFMO significantly improved OS cell chemosensitivity to CDP and DOX.
Conclusions:
- Metabolites produced by apoptotic cells, such as SPD, play a critical role in treatment resistance.
- Targeting SPD biosynthesis represents a potential therapeutic strategy to enhance chemotherapy effectiveness in osteosarcoma.
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