Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan.
Department of Sport Performance, National Taiwan University of Sport, 16, Sec. 1, Shuang-Shih Road, Taichung 40404, Taiwan.
J Food Drug Anal. 2019 Oct;27(4):887-896. doi: 10.1016/j.jfda.2019.07.001. Epub 2019 Aug 21.
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 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 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.
受体晚期糖基化终产物（RAGE）触发胰腺癌中吉西他滨（GEM）耐药已得到证实。因此，寻找一种安全有效的辅助药物来预防胰腺癌的进展是至关重要的。槲皮素是一种在苹果、葡萄、红覆盆子和洋葱中含量丰富的类黄酮，已被报道可抑制 RAGE。本研究旨在探讨通过减少 RAGE 调节细胞死亡和增强药物作用的机制，特别是在 GEM 耐药的胰腺癌细胞中。我们的结果表明，通过 RAGE 特异性 siRNA 转染沉默 RAGE 表达，通过抑制 PI3K/AKT/mTOR 轴，显著增加细胞凋亡、自噬和 GEM 诱导的细胞毒性，在 MIA Paca-2 和 MIA Paca-2（GEM 耐药细胞）中。值得注意的是，槲皮素表现出与 RAGE 沉默相似的显著效果，可有效减弱 RAGE 表达，促进 MIA Paca-2 细胞的细胞周期停滞、自噬、凋亡和 GEM 化疗敏感性，表明在联合使用槲皮素和 GEM 治疗时发生了额外的反应。总之，这些结果表明，槲皮素在调节胰腺癌细胞中细胞凋亡和自噬相关途径以及增加 GEM 化疗敏感性的分子机制涉及抑制 RAGE 表达。
