The PI3K-Akt mediates oncogenic Met-induced centrosome amplification and chromosome instability.
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.
Nam
Hyun-Ja
HJ
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea.
Chae
Sunyoung
S
Jang
Seung-Hoon
SH
Cho
Hyeseong
H
Lee
Jae-Ho
JH
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism*; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D018385:Centrosome / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D043171:Chromosomal Instability; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017978:Receptors, Growth Factor / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D019870:1-Phosphatidylinositol 4-Kinase; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D034741:RNA, Small Interfering; D017978:Receptors, Growth Factor; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C491743:MET protein, human