Targeted PLK1 suppression through RNA interference mediated by high-fidelity Cas13d mitigates osteosarcoma progression via TGF-ß/Smad3 signalling.
J Cell Mol Med
; 28(10): e18400, 2024 May.
Article
in En
| MEDLINE
| ID: mdl-38780513
ABSTRACT
Osteosarcoma is the most common primary bone malignancy in children and adolescents. Overexpression of polo-like kinase 1 (PLK1) is frequent in osteosarcoma and drives disease progression and metastasis, making it a promising therapeutic target. In this study, we explored PLK1 knockdown in osteosarcoma cells using RNA interference mediated by high-fidelity Cas13d (hfCas13d). PLK1 was found to be significantly upregulated in osteosarcoma tumour tissues compared to normal bone. sgRNA-mediated PLK1 suppression via hfCas13d transfection inhibited osteosarcoma cell proliferation, induced G2/M cell cycle arrest, promoted apoptosis, reduced cell invasion and increased expression of the epithelial marker E-cadherin. Proximity labelling by TurboID coupled with co-immunoprecipitation identified novel PLK1 interactions with Smad3, a key intracellular transducer of TGF-ß signalling. PLK1 knockdown impaired Smad2/3 phosphorylation and modulated TGF-ß/Smad3 pathway inactivation. Finally, in vivo delivery of hfCas13d vectors targeting PLK1 substantially attenuated osteosarcoma xenograft growth in nude mice. Taken together, this study highlights PLK1 as a potential therapeutic target and driver of disease progression in osteosarcoma. It also demonstrates the utility of hfCas13d-mediated gene knockdown as a strategy for targeted therapy. Further optimization of PLK1 suppression approaches may ultimately improve clinical outcomes for osteosarcoma patients.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Signal Transduction
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Osteosarcoma
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Transforming Growth Factor beta
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Proto-Oncogene Proteins
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Protein Serine-Threonine Kinases
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Apoptosis
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Cell Cycle Proteins
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RNA Interference
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Cell Proliferation
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Smad3 Protein
Limits:
Animals
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Humans
Language:
En
Year:
2024
Type:
Article