The Blocking of c-Met Signaling Induces Apoptosis through the Increase of p53 Protein in Lung Cancer.
OBJECTIVE
c-Met is an attractive potential target for novel therapeutic inhibition of human cancer, and c-Met tyrosine kinase inhibitors (TKIs) are effective growth inhibitors of various malignancies. However, their mechanisms in anticancer effects are not clear. In the present study, we investigated the possibility that blocking c-Met signaling induces p53-mediated growth inhibition in lung cancer.


METHODS
The growth inhibitory effects of c-Met TKI (SU11274) on lung cancer cells and a xenograft model were assessed using the MTT assay, flow cytometry, and terminal deoxyribonucleotide transferase-mediated nick-end labeling staining. The role of p53 protein in the sensitivity of c-Met TKI (SU11274) was examined by Western blot analysis and immunohistochemistry.


RESULTS
SU11274 significantly induced apoptosis in A549 cells with wild-type p53, compared with that in Calu-1 cells with null-type p53. SU11274 increased p53 protein by enhancing the stability of p53 protein. Increased p53 protein by SU11274 induced up-regulation of Bax and PUMA expression and down-regulation of Bcl-2 expression, subsequently activating caspase 3. In p53 knock-out and knock-in systems, we confirmed that SU11274 caused apoptosis through the p53-mediated apoptotic pathway. Likewise, in the A549 xenograft model, SU11274 effectively shrank tumor volume and induced apoptosis via increased p53 protein expression. Blocking c-Met signaling increased the level of p53 protein.


CONCLUSIONS
Our finding suggested that p53 plays an important role in SU11274-induced apoptosis, and p53 status seems to be related to the sensitivity to SU11274 in lung cancer.
Brain Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, Korea. ; Genomic Research Center for Lung and Breast/Ovarian Cancers, Korea University College of Medicine, Seoul, Korea.
Hae-Yun
HY
Jung
Hyun-Jung
HJ
Joo
Jong Kuk
JK
Park
Yeul Hong
YH
Kim
((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2; 3-dihydro-1H-indole-5-sulfonamide); Apoptosis; Lung neoplasms; Molecular targeted therapy; Tumor suppressor protein p53