Lucidone inhibits autophagy and MDR1 via HMGB1/RAGE/PI3K/Akt signaling pathway in pancreatic cancer cells.

Abstract

Gemcitabine (GEM) drug resistance remains a difficult challenge in pancreatic ductal adenocarcinoma (PDAC) treatment. Therefore, identifying a safe and effective treatment strategy for PDAC is urgent. Lucidone is a natural compound extracted from the fruits of Lindera erythrocarpa Makino. However, the role of lucidone in PDAC inhibition remains unclear. In addition, high-mobility group box 1 (HMGB1) and receptor for advanced glycation end products (RAGE) are involved in multidrug resistance protein 1 (MDR1) regulation and GEM resistance. Thus, this study aimed to explore the function of lucidone in tumor cytotoxicity and chemosensitivity through the suppression of RAGE-initiated signaling in PDAC cells. The data showed that lucidone significantly promoted apoptotic cell death and inhibited the expression of autophagic proteins (Atg5, Beclin-1, LC3-II, and Vps34) and MDR1 by inhibiting the HMGB1/RAGE/PI3K/Akt axis in both MIA Paca-2 cells and MIA Paca-2GEMR cells (GEM-resistant cells). Notably, convincing data were also obtained in experiments involving RAGE-specific siRNA transfection. In addition, remarkable cell proliferation was observed after treatment with lucidone combined with GEM, particularly in MIA Paca-2GEMR cells, indicating that lucidone treatment enhanced chemosensitivity. Collectively, this study provided the underlying mechanism by which lucidone treatment inhibited HMGB1/RAGE-initiated PI3K/Akt/MDR1 signaling and consequently enhanced chemosensitivity in PDAC.

• Authors: Sheng-Yi Chen, Yi-Hao Hsu, Sheng-Yang Wang, Ying-Yin Chen, Cheng-Jie Hong, Gow-Chin Yen
• Journal: Phytotherapy research : PTR (Phytother Res) Vol. 36 Issue 4 Pg. 1664-1677 (Apr 2022) ISSN: 1099-1573 [Electronic] England
• PMID: 35224793 (Publication Type: Journal Article)
• Copyright: © 2022 John Wiley & Sons Ltd.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Cyclopentanes
• HMGB1 Protein
• Receptor for Advanced Glycation End Products
• lucidone
• Proto-Oncogene Proteins c-akt

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Autophagy
• Carcinoma, Pancreatic Ductal
• Cell Line, Tumor
• Cyclopentanes
• HMGB1 Protein
• Humans
• Pancreatic Neoplasms (pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor for Advanced Glycation End Products
• Signal Transduction
• Pancreatic Neoplasms