Abstract 2857: Asparagine synthetase regulate β-catenin dependent lung cancer metastasis

Objective: Lung cancer was a malignant tumor with high morbidity and mortality. The lead cause of lung cancer-related death was metastasis. Asparagine synthetase (ASNS) that was a key enzyme to convert glutamine to asparagine played important role in cell metabolism. Based on previous metabolomics data, the high level of asparagine synthase was significantly correlated with tumor metastasis. The purpose of this study was to investigate the role of asparagine synthase in lung cancer metastasis, furthermore for anti-cancer target therapy. Method: For pursuing high ASNS correlated to metastasis, a cohort were collected from Xiangya hospital. And selected paired lung cancer cell lines were used for discovering potential molecular interactions. Importantly, some key molecules or pathways were found by cell biology study and bioinformatics analysis. In the part of cellular and molecule study, Transwell, scratch test, Western blot, immunofluorescence, immunohistochemistry and co-immunoprecipitation experiments were used. The results of the inquiry were validated by using a mouse metastasis model. Results: With provided from Xiangya hospital and TCGA cohort, we could validate high ASNS had relations to patient's metastasis and survival. In part of cell biology study, high wild-type ASNS could promote lung cancer cell metastasis and proliferation in vivo and vitro. Overexpression of amidotransferase-dysfunction ASNS had partially potential to drive metastasis but have nothing to increase cell proliferation. Furthermore, Wnt/β-catenin cascades were responsible for tumor mestasis among wild-type and amidotransferase-mutated type groups. The accumulation and nuclear location of β-catenin definitely depend on high ASNS expression even with amidotransferase mutation. With processing, ASNS possible interacted with key proteins located in Wnt/β-catenin signaling pathway to mediate signal conduction. But the activation of ASNS amidotransferase was necessary to promoted tumor proliferation. Conclusion: ASNS promoted metastasis by mediating Wnt/β-catenin signaling conduction even without ASNS amidotransferase activity, while cell proliferation was required for amidotransferase function. Maybe dual inhibition of ASNS and Wnt/β-catenin would be an effective target for anti-tumor metastasis and proliferation. Key Words: ASNS, metastasis, lung cancer, β-catenin Citation Format: Dong-Jing Cai, Cheng-Ping Hu, Li li, Zi-Yu Zhang, Yuan-Mao Li, Min Li. Asparagine synthetase regulate β-catenin dependent lung cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2857.