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The PI3K-Akt mediates oncogenic Met-induced centrosome amplification and chromosome instability

Hyun-Ja Nam1, Sunyoung Chae, Seung-Hoon Jang

  • 1Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.

Carcinogenesis
|June 30, 2010
PubMed

Insights

Aberrant hepatocyte growth factor/Met signaling drives cancer by causing centrosome amplification and chromosomal instability (CIN) through the PI3K-Akt pathway, particularly in p53-deficient cells.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Molecular Oncology

Background:

  • Aberrant hepatocyte growth factor receptor (Met) signaling is a known oncogenic driver.
  • Genomic instability is increasingly recognized as a critical factor in tumorigenesis.
  • The link between Met signaling, centrosome abnormalities, and genomic instability remains unclear.

Purpose of the Study:

  • To investigate whether oncogenic Met signaling is associated with centrosome abnormalities and genomic instability.
  • To elucidate the molecular pathways involved in Met-induced genomic instability.

Main Methods:

  • Expression of constitutive active Met (CA-Met) in HCT116 cells.
  • Treatment with LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor.
  • Knockdown of Akt using small interfering RNAs.
  • Overexpression of phosphatase and tensin homolog (PTEN) or dominant-negative Akt.
  • Analysis of centrosome number, spindle formation, aneuploidy, and chromosomal instability (CIN) in p53(+/+) and p53(-/-) HCT116 cells.

Main Results:

  • CA-Met expression led to supernumerary centrosomes and aneuploidy, indicative of deregulated centrosome duplication.
  • The PI3K-Akt pathway, specifically Akt signaling, was found to be crucial for Met-induced supernumerary centrosome formation.
  • CA-Met expression significantly increased aneuploidy in p53(-/-) HCT116 cells but not in p53(+/+) cells, highlighting the role of p53 status in Met-induced CIN.
  • Aberrant Met signaling induces centrosome amplification and CIN via the PI3K-Akt pathway.

Conclusions:

  • Oncogenic Met signaling promotes centrosome amplification and chromosomal instability (CIN).
  • The PI3K-Akt pathway is a key mediator of Met-induced centrosome abnormalities and CIN.
  • The oncogenic effects of Met signaling on genomic instability are influenced by p53 status.

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