The PI3K-Akt mediates oncogenic Met-induced centrosome amplification and chromosome instability.
Nam, HJ; Chae, S; Jang, SH; Cho, H; Lee, JH
Carcinogenesis, 31(9):1531-1540, 2010
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.
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