Quercetin facilitates cell death and chemosensitivity through RAGE/PI3K/AKT/mTOR axis in human pancreatic cancer cells

Chieh-Yu Lan ^a,1, Sheng-Yi Chen ^a,1, Chia-Wen Kuo ^a, Chi-Cheng Lu ^b, Gow-Chin Yen ^a,*

a Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan

b Department of Sport Performance, National Taiwan University of Sport, 16, Sec. 1, Shuang-Shih Road, Taichung 40404, Taiwan

The triggering of gemcitabine (GEM) drug resistance in pancreatic cancer by the receptor for advanced glycation end products (RAGE) has been demonstrated. Hence, finding a safe and effective adjuvant for preventing pancreatic cancer progression is imperative. Quercetin is a flavonoid that is abundant in apples, grapes, red raspberry, and onions and has been reported to inhibit RAGE. This research aimed to investigate the mechanisms of quercetin in regulating cell death and enhancing drug effects through RAGE reduction, especially in GEM-resistant pancreatic cancer cells. Our results showed that silencing RAGE expression by RAGE-specific siRNA transfection significantly increased cell death by apoptosis, autophagy and GEM-induced cytotoxicity by suppressing the PI3K/AKT/mTOR axis in MIA Paca-2 and MIA Paca-2 GEMR cells (GEM-resistant cells). Notably, quercetin showed a dramatic effect similar to RAGE silencing that effectively attenuated RAGE expression to facilitate cell cycle arrest, autophagy, apoptosis, and GEM chemosensitivity in MIA Paca-2 GEMR cells, suggesting that an additional reaction occurred under combined quercetin and GEM treatment. In conclusion, the results demonstrated that the molecular mechanisms of quercetin in regulating apoptosis and autophagy-related pathways and increasing GEM chemosensitivity in pancreatic cancer cells involved inhibition of RAGE expression.

Keywords: Autophagy; Gemcitabine resistance; Pancreatic cancer; Quercetin; RAGE

https://doi.org/10.1016/j.jfda.2019.07.001.

(http://www.sciencedirect.com/science/article/pii/S1021949819300705)