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Aya Shiba
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P1.03 - Biology (Not CME Accredited Session) (ID 935)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.03-20 - The Novel SFN Inhibitors Aprepitant and Ticagrelor Exert Anti-Tumor Effects Through Blocking of Oncoprotein Ubiquitination (ID 12110)
16:45 - 18:00 | Presenting Author(s): Aya Shiba
- Abstract
Background
We have previously shown that the gene encoding stratifin (SFN, 14-3-3 sigma) is differentially expressed during the course of progression from AIS to early invasive adenocarcinoma (eIA), inducing early tumor progression by binding to SKP1 and blocking the activity of SCFFBW7 ubiquitin ligase. As suppression of SFN significantly reduces cell growth and tumor formation or progression, we expected that inhibition of SFN could be a promising therapeutic strategy for lung adenocarcinoma.
a9ded1e5ce5d75814730bb4caaf49419 Method
To identify candidate compounds that bind specifically to SFN and block SFN-SKP1 binding, we carried out in silico library screening based on putative druggable sites of SFN around the SKP1 interaction interface using molecular docking against 7,133 bioactive compounds from the DrugBank database. Experimental validation was performed for 46 compounds that showed the highest docking scores. Cell growth and dissociation of SFN-SKP1 were examined by WST-8 assay and IP/western blotting after treatment with each compound. Finally, 4 candidate compounds were subjected to in vivo evaluation. Tumor-bearing mice that had received subcutaneous injection of A549 cells were subjected to two experimental schedules: 1) Daily oral administration of each compound starting at 1 day after injection until 21 days. 2) Same as 1) but starting when the tumors had reached 100 mm3 in size.
4c3880bb027f159e801041b1021e88e8 Result
Through in silico screening and experimental validation, we identified 4 compounds as SFN inhibitors: Aprepitant, Ticagrelor, Ezetimibe, and Chlorhexidine. All of them significantly and dose dependently reduced cell growth and SFN-SKP1 binding. Notably, Aprepitant completely blocked in vivo tumor formation, and Ticagrelor markedly reduced tumor progression when administered from the day after tumor cell injection. Furthermore, Aprepitant and Ticagrelor reduced tumor progression in a dose-dependent manner even when administration was started after tumors had grown to 100 mm3.
8eea62084ca7e541d918e823422bd82e Conclusion
Here we have shown that inhibition of SFN-SKP1 binding results in an anti-tumor effect. Since SFN binding to SKP1 results in SCFFBW7 dysfunction and allows oncoproteins such as cyclin E1 and c-Jun to evade ubiquitination and subsequent degradation, it is considered that inhibition of SFN will lead to ubiquitination of these oncoproteins. Although Aprepitant is a NK-1R (neurokinin-1 receptor) antagonist which is already approved as an antiemetic drug, and Ticagrelor is a reversible P2Y12 inhibitor exerting an anti-platelet effect, our results suggest that these agents could be applicable for treatment of lung adenocarcinoma.
As overexpression of SFN starts from eIA, we believe that SFN inhibitors will provide a novel chemotherapeutic strategy for early-stage lung adenocarcinoma.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P1.09 - Pathology (Not CME Accredited Session) (ID 941)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.09-30 - Heterotopic Expression of Ceruloplasmin in Lung Adenocarcinoma and its Possible Clinical Use as a Tumor Biomarker (ID 12100)
16:45 - 18:00 | Author(s): Aya Shiba
- Abstract
Background
Ceruloplasmin (CP) is a well-known copper binding protein synthesized mainly in the liver, and its expression is well known to be elevated in the serum of cancer patients and in malignant tumor cells. Lung cancer is the leading cause of cancer-related death worldwide, and adenocarcinoma is the main histological type of lung cancer. Previously, we reported that the expression of CP mRNA was significantly higher in early but invasive adenocarcinoma than in adenocarcinoma in situ (AIS) on the basis of cDNA microarray analysis (Shiba, Int. J. Cancer 2011). However, the role of CP in lung adenocarcinoma is still unclear. Here, we examined and compared the expression of CP in various histological subtypes of lung adenocarcinoma and its correlation with patient outcome.
a9ded1e5ce5d75814730bb4caaf49419 Method
CP expression in resected specimens of lung adenocarcinoma and lung adenocarcinoma cell lines was determined using quantitative real-time RT-PCR and western blot analysis. Immunohistochemistry for CP was carried out using 196 specimens of lung adenocarcinoma and we divided the cases into a high expression group (H-score >90: 92 cases) and a low expression group (H-score <90: 104 cases).
4c3880bb027f159e801041b1021e88e8 Result
CP expression was significantly higher in invasive adenocarcinoma than in AIS. The high expression group had a significantly poorer outcome than the low expression group (p＜0.01) and high expression of CP was also correlated with pathological stage, pT, and pN (p＜0.01). Multivariate analysis showed that CP expression was an independent prognostic factor in lung adenocarcinoma patients (HR 1.642, 95％CI 1.050-2.568, p＝0.030). CP secreted from cancer cells was also detected by western blot analysis the medium used for culture of lung adenocarcinoma cell lines.
8eea62084ca7e541d918e823422bd82e Conclusion
CP is produced heterotopically by lung adenocarcinoma cells and its expression is associated with tumor progression. In view of the presence of the secreted form of CP in tumor cells, CP may be a useful biomarker for lung adenocarcinoma.
6f8b794f3246b0c1e1780bb4d4d5dc53
