Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Antiproliferative Activity of Piceamycin by Regulating Alpha-Actinin-4 in Gemcitabine-Resistant Pancreatic Cancer Cells

  • Jee-Hyung Lee (Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University) ;
  • Jin Ho Choi (Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kyung-Min Lee (Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University) ;
  • Min Woo Lee (Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University) ;
  • Ja-Lok Ku (Department of Biomedical Sciences, Korean Cell Line Bank, Laboratory of Cell Biology and Cancer Research Institute, College of Medicine, Seoul National University) ;
  • Dong-Chan Oh (Natural Products Research Institute, College of Pharmacy, Seoul National University) ;
  • Yern-Hyerk Shin (Natural Products Research Institute, College of Pharmacy, Seoul National University) ;
  • Dae Hyun Kim (Dxome Co. Ltd.) ;
  • In Rae Cho (Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University) ;
  • Woo Hyun Paik (Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University) ;
  • Ji Kon Ryu (Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University) ;
  • Yong-Tae Kim (Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University) ;
  • Sang Hyub Lee (Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University) ;
  • Sang Kook Lee (Natural Products Research Institute, College of Pharmacy, Seoul National University)
  • Received : 2023.06.07
  • Accepted : 2023.07.05
  • Published : 2024.01.01
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Abstract

Although gemcitabine-based regimens are widely used as an effective treatment for pancreatic cancer, acquired resistance to gemcitabine has become an increasingly common problem. Therefore, a novel therapeutic strategy to treat gemcitabine-resistant pancreatic cancer is urgently required. Piceamycin has been reported to exhibit antiproliferative activity against various cancer cells; however, its underlying molecular mechanism for anticancer activity in pancreatic cancer cells remains unexplored. Therefore, the present study evaluated the antiproliferation activity of piceamycin in a gemcitabine-resistant pancreatic cancer cell line and patient-derived pancreatic cancer organoids. Piceamycin effectively inhibited the proliferation and suppressed the expression of alpha-actinin-4, a gene that plays a pivotal role in tumorigenesis and metastasis of various cancers, in gemcitabine-resistant cells. Long-term exposure to piceamycin induced cell cycle arrest at the G0/G1 phase and caused apoptosis. Piceamycin also inhibited the invasion and migration of gemcitabine-resistant cells by modulating focal adhesion and epithelial-mesenchymal transition biomarkers. Moreover, the combination of piceamycin and gemcitabine exhibited a synergistic antiproliferative activity in gemcitabine-resistant cells. Piceamycin also effectively inhibited patient-derived pancreatic cancer organoid growth and induced apoptosis in the organoids. Taken together, these findings demonstrate that piceamycin may be an effective agent for overcoming gemcitabine resistance in pancreatic cancer.

Keywords

Acknowledgement

This research was supported by the Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (0720213063) and by the MSIT (2021R1A4A2001251).

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