Journal Article

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

Hyun-Ja Nam, Sunyoung Chae, Seung-Hoon Jang, Hyeseong Cho and Jae-Ho Lee

in Carcinogenesis

Volume 31, issue 9, pages 1531-1540
Published in print September 2010 | ISSN: 0143-3334
Published online June 2010 | e-ISSN: 1460-2180 | DOI:
The PI3K–Akt mediates oncogenic Met-induced centrosome amplification and chromosome instability

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The oncogenic ability of aberrant hepatocyte growth factor receptor (Met) signaling is thought to mainly rely on its mitogenic and anti-apoptotic effects. Recently, however, cumulating evidences suggest that genomic instability may be a crucial factor in tumorigenesis. Here, we address whether oncogenic Met receptor is linked to the centrosome abnormality and genomic instability. We showed that expression of the constitutive active Met (CA-Met) induced supernumerary centrosomes probably due to deregulated centrosome duplication, which was accompanied with multipolar spindle formation and aneuploidy. Interestingly, LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, significantly suppressed the appearance of supernumerary centrosomes. Moreover, knockdown of Akt with small interfering RNAs and overexpression of phosphatase and tensin homolog or dominant-negative Akt abrogated supernumerary centrosome formation, evidencing the involvement of PI3K signaling. We further showed that expression of CA-Met significantly increased aneuploidy in p53−/− HCT116 cells, but not in p53+/+ HCT116 cells, indicating that the ability of CA-Met to induce chromosomal instability (CIN) phenotype is related with p53 status. Together, our data demonstrate that aberrant hepatocyte growth factor/Met signaling induces centrosome amplification and CIN via the PI3K–Akt pathway, providing an example that oncogenic growth factor signals prevalent in a wide variety of cancers have cross talks to centrosome abnormality and CIN.

Journal Article.  6257 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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