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.

中文翻译：

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槲皮素通过人胰腺癌细胞中的 RAGE/PI3K/AKT/mTOR 轴促进细胞死亡和化学敏感性

已证实晚期糖基化终产物 (RAGE) 受体可引发胰腺癌中的吉西他滨 (GEM) 耐药性。因此，寻找一种安全有效的预防胰腺癌进展的佐剂势在必行。槲皮素是一种黄酮类化合物，富含于苹果、葡萄、红树莓和洋葱中，据报道可抑制 RAGE。本研究旨在探讨槲皮素通过减少 RAGE 调节细胞死亡和增强药物作用的机制，特别是在 GEM 耐药胰腺癌细胞中的作用。我们的研究结果表明，通过 RAGE 特异性 siRNA 转染沉默 RAGE 表达，通过抑制 MIA Paca-2 和 MIA Paca-2 GEMR 细胞（GEM-抗性细胞）。值得注意的是，槲皮素显示出类似于 RAGE 沉默的显着效果，可有效减弱 RAGE 表达以促进 MIA Paca-2 GEMR 细胞中的细胞周期停滞、自噬、凋亡和 GEM 化学敏感性，这表明在槲皮素和 GEM 联合治疗下发生了额外的反应。总之，结果表明槲皮素在调节胰腺癌细胞凋亡和自噬相关途径以及增加 GEM 化学敏感性方面的分子机制涉及抑制 RAGE 表达。