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Targeting the centrosome and polo-like kinase 4 in osteosarcoma

Fergal C Kelleher1,2, Jeska Kroes1, Jeremy Lewin3

  • 1Department of Medical Oncology, St. James Hospital, Dublin, Ireland.

Carcinogenesis
|December 4, 2018
PubMed

Insights

Extra centrosomes, driven by polo-like kinase 4 (PLK4), promote tumorigenesis and aneuploidy. Functional p53 halts cell cycle in response, suggesting PLK4 inhibitors like CFI-400945 may treat osteosarcomas.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Genetics

Background:

  • The role of extra centrosomes in tumorigenesis has been debated.
  • Polo-like kinase 4 (PLK4) overexpression induces centrosome amplification and aneuploidy.
  • Centrosome amplification is linked to spontaneous tumor formation in mice.

Purpose of the Study:

  • To investigate the link between PLK4, centrosome amplification, and tumorigenesis.
  • To explore the role of p53 in response to extra centrosomes.
  • To evaluate the potential of PLK4 inhibitors in osteosarcoma treatment.

Main Methods:

  • Overexpression of PLK4 to induce centrosome amplification.
  • Analysis of cellular aneuploidy and tumor formation in mice.
  • Investigation of p53 pathway activation and cell cycle arrest.
  • Examination of osteosarcoma tissues for associated genetic features.

Main Results:

  • PLK4 overexpression leads to centrosome amplification, aneuploidy, and tumorigenesis.
  • p53-deficient tissues tolerate extra centrosomes, while p53-proficient tissues arrest proliferation.
  • Extra centrosomes activate the PIDDosome complex, leading to p53 stabilization and cell cycle arrest.
  • Osteosarcomas exhibit aneuploidy, chromosomal rearrangements, and p53 dysfunction.

Conclusions:

  • PLK4-induced centrosome amplification is a driver of tumorigenesis.
  • The p53 pathway acts as a critical barrier against extra centrosomes.
  • PLK4 inhibitors, such as CFI-400945, show potential therapeutic value for osteosarcoma.

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