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Targeted PLK1 suppression through RNA interference mediated by high-fidelity Cas13d mitigates osteosarcoma

Yi Yuan1,2,3, Daigui Cao1, Anwei Zhang1,2

  • 1Department of Orthopedics, Chongqing General Hospital, Chongqing, China.

Journal of Cellular and Molecular Medicine
|May 23, 2024
PubMed

Insights

Polo-like kinase 1 (PLK1) drives osteosarcoma progression. Targeting PLK1 with high-fidelity Cas13d (hfCas13d) inhibited tumor growth, reduced metastasis, and showed therapeutic potential in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Therapy

Background:

  • Osteosarcoma is a common pediatric bone cancer.
  • Overexpression of polo-like kinase 1 (PLK1) is linked to osteosarcoma progression and metastasis.
  • PLK1 presents a potential therapeutic target for osteosarcoma.

Purpose of the Study:

  • To investigate the efficacy of PLK1 knockdown using high-fidelity Cas13d (hfCas13d) in osteosarcoma.
  • To elucidate the molecular mechanisms underlying PLK1's role in osteosarcoma.
  • To evaluate the therapeutic potential of hfCas13d-mediated PLK1 targeting in vivo.

Main Methods:

  • Utilized RNA interference with hfCas13d to suppress PLK1 expression in osteosarcoma cells.
  • Assessed effects on cell proliferation, cell cycle, apoptosis, and invasion.
  • Employed proximity labeling and co-immunoprecipitation to identify protein interactions.
  • Administered hfCas13d vectors targeting PLK1 in osteosarcoma xenograft models.

Main Results:

  • PLK1 was significantly upregulated in osteosarcoma tissues.
  • hfCas13d-mediated PLK1 knockdown inhibited proliferation, induced cell cycle arrest, promoted apoptosis, and reduced invasion.
  • Identified novel PLK1 interaction with Smad3, impacting TGF-β/Smad3 signaling.
  • In vivo delivery of hfCas13d targeting PLK1 reduced xenograft tumor growth.

Conclusions:

  • PLK1 is a key driver of osteosarcoma progression and metastasis.
  • hfCas13d-mediated PLK1 knockdown is a viable therapeutic strategy for osteosarcoma.
  • Targeting PLK1 offers potential for improved clinical outcomes in osteosarcoma patients.
Keywords:
PLK1Smad3hfCas13dosteosarcoma

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