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-2 GEMR 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-2 GEMR 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.

Matrix stiffness triggers chemoresistance through elevated autophagy in pancreatic ductal adenocarcinoma

“…In pancreatic cancer, an increasing body of evidence suggests that autophagy plays an essential role in triggering gemcitabine chemoresistance. 67,68 To investigate whether autophagy induced by substrate stiffness is involved in the chemoresistance of PANC-1 and MIA-PaCa2, the changes in the gene and protein expression levels of the ABC transporter family-related genes ABCC1, ABCC3, ABCC10, and ABCG2 were examined, by inhibiting or activating autophagy with rapamycin and chloroquine. Previous experimental results have shown that in PANC-1 and MIA-PaCa2 cells cultured on hydrogels, soft substrate group exhibited low autophagy level, while stiff substrate group showed high autophagy level.…”

HMGB1/RAGE axis in tumor development: unraveling its significance

“…Further experiments reveal that lucidone significantly inhibits the protein levels of HMGB1 and RAGE in GEM-resistant pancreatic cancer cells. In conclusion, lucidone promotes apoptosis in human pancreatic cancer cells through the HMGB1-RAGE axis ( 110 ) ( Figure 3 ).…”

“…demonstrated that 4-AAQB downregulates autophagy through inhibition of the HMGB1/RAGE-initiated PI3K/Akt/MDR1 signaling pathway ( 104 ). They also showed that lucidone combined with gemcitabine reduces autophagy and promotes cell apoptosis through the HMGB1/RAGE/PI3K/Akt signaling pathway, thereby slowing down the development of pancreatic cancer ( 110 ). Currently, besides surgery, the main treatment methods for patients with exocrine pancreatic cancer in clinical practice are radiotherapy and chemotherapy, which can significantly activate autophagy in pancreatic cancer cells ( 135 , 136 ).…”

Autophagic mechanisms in longevity intervention: role of natural active compounds

“…Lucidone, a terpeneoid, inhibited autophagy via HMGB1/RAGE/PI3K/Akt signalling pathway in pancreatic cancer cells (Ref. 175 ). Celastrol induced autophagy by targeting AR/miR-101 and served as epigenetic regulator in prostate cancer cell lines (Ref.…”