PNU-74654 Induces Cell Cycle Arrest and Inhibits EMT Progression in Pancreatic Cancer

  • Medicina (Kaunas). 2023 Aug 24;59(9):1531. doi: 10.3390/medicina59091531.
Tai-Long Chien  1 ,  Yao-Cheng Wu  2 ,  Hsiang-Lin Lee  2  3  4 ,  Wen-Wei Sung  2  3  5 ,  Chia-Ying Yu  2  5 ,  Ya-Chuan Chang  2  5 ,  Chun-Che Lin  2  3  6 ,  Chi-Chih Wang  2  3  6 ,  Ming-Chang Tsai  2  3  6
Affiliations
  • 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.
PMID: 37763649 DOI: 10.3390/medicina59091531
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.

Keywords
WNT; cell cycle arrest; migration; pancreatic adenocarcinoma; β-catenin.
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