PNU-74654 Induces Cell Cycle Arrest and Inhibits EMT Progression in Pancreatic Cancer
Author:
Chien Tai-Long1, Wu Yao-Cheng2, Lee Hsiang-Lin234, Sung Wen-Wei235ORCID, Yu Chia-Ying25, Chang Ya-Chuan25ORCID, Lin Chun-Che236, Wang Chi-Chih236ORCID, Tsai Ming-Chang236
Affiliation:
1. Department of Gastroenterology, Antai Medical Care Corporation Antai Tian-Sheng Memorial Hospital, Pingtung 928, Taiwan 2. School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan 3. Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan 4. Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan 5. Department of Urology, Chung Shan Medical University Hospital, Taichung 402, Taiwan 6. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
Abstract
Background and Objectives: PNU-74654, a Wnt/β-catenin pathway inhibitor, has an antiproliferative effect on many cancer types; however, its therapeutic role in pancreatic cancer (PC) has not yet been demonstrated. Here, the effects of PNU-74654 on proliferation and cell cycle phase distribution were studied in PC cell lines. Materials and Methods: The cancer-related molecular pathways regulated by PNU-74654 were determined by a proteome profiling oncology array and confirmed by western blotting. Results: The cell viability and proliferative ability of PC cells were decreased by PNU-74654 treatment. G1 arrest was observed, as indicated by the downregulation of cyclin E and cyclin-dependent kinase 2 (CDK2) and the upregulation of p27. PNU-74654 inhibited the epithelial–mesenchymal transition (EMT), as determined by an increase in E-cadherin and decreases in N-cadherin, ZEB1, and hypoxia-inducible factor-1 alpha (HIF-1α). PNU-74654 also suppressed cytoplasmic and nuclear β-catenin and impaired the NF-κB pathway. Conclusions: These results demonstrate that PNU-74654 modulates G1/S regulatory proteins and inhibits the EMT, thereby suppressing PC cell proliferation, migration, and invasion. The synergistic effect of PNU-74654 and chemotherapy or the exclusive use of PNU-74654 may be therapeutic options for PC and require further investigation.
Funder
Chung Shan Medical University
Reference50 articles.
1. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries;Sung;CA Cancer J. Clin.,2021 2. Pancreatic cancer;Mizrahi;Lancet,2020 3. Cancer Statistics, 2021;Siegel;CA Cancer J. Clin.,2021 4. Lee, H.L., Peng, C.M., Huang, C.Y., Wu, S.Y., Tsai, M.C., Wang, C.C., Chen, S.L., Lin, C.C., Huang, C.N., and Sung, W.W. (2018). Is mortality-to-incidence ratio associated with health disparity in pancreatic cancer? A cross-sectional database analysis of 57 countries. BMJ Open, 8. 5. Kleeff, J., Korc, M., Apte, M., La Vecchia, C., Johnson, C.D., Biankin, A.V., Neale, R.E., Tempero, M., Tuveson, D.A., and Hruban, R.H. (2016). Pancreatic cancer. Nat. Rev. Dis. Prim., 2.
|
|