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S. Takikawa
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-047 - The Inhibitory Effects of CDK4 and MDM2 on Migration and Invasion in Human Non-Small Cell Lung Cancer Cells (ID 2833)
09:30 - 17:00 | Author(s): S. Takikawa
- Abstract
Background:
Cyclin-dependent kinase 4 (CDK4)/RB and mouse double minute 2 (MDM2)/p53 are the two main regulators of the tumor-suppressor pathways that control cellular responses to potentially oncogenic stimuli. CDK4 inhibits RB by triggering its phosphorylation, leading to releasing the G1-S restriction point. MDM2 inhibits the transcription activity of p53 by blocking the transfer of p53 from cytoplasm to nucleus and by accelerating ubiquitination of p53. Our preliminary SNP microarray analysis using lung specimens from non-invasive tumor (adenocarcinoma in situ) and invasive tumor (lepidic predominant adenocarcinoma) showed the amplification of chromosome 12q13–15, including CDK4 and MDM2 gene regions. The aim of the present study was to determine the mechanistic implications of CDK4 and MDM2 in lung adenocarcinoma migration and invasion.
Methods:
Using siRNAs specific for CDK4 and MDM2, the expressions of CDK4 and MDM2 were knocked down in the human non-small cell lung cancer cell lines A549, H460, H1299, SK-Lu-1 and H23, which harbor wild-type RB yet contain other aberrations in p53 (wild-type in A549, H460, absent in H1299, and mutated in SK-Lu-1, H23). Cell proliferation (AlamarBlue staining), mobility (scratch assay), and invasion (transwell-matrigel chamber system) were investigated.
Results:
The knockdown of CDK4 (5.5, 18.5, 2.2, 22.8 and 8.3% compared to scrambled siRNA in A549, H460, H1299, SK-Lu-1 and H23, respectively) significantly inhibited cell proliferation in H23 and SK-Lu-1, and decreased cell migration in SK-Lu-1 and H460. It also repressed cell invasion in H460, SK-Lu-1 and A549. The decreased expression of MDM2 (43.4, 69.6, 6.4, 27.3, 8.7% compared to scrambled siRNA in A549, H460, H1299, SK-Lu-1 and H23, respectively) dramatically inhibited cell proliferation in H1299, SK-Lu-1 and H23, and diminished cell migration in H23, A549 and SK-Lu-1. It also hindered cell invasion in H460 and H23.
Conclusion:
These findings suggest CDK4 and/or MDM2 pathways may play critical roles in cell proliferation, mobility and invasion, and furthermore, the targeting CDK4 and/or MDM2 may provide therapeutic benefit to lung cancer patients.
