CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Tiliroside disrupted iron homeostasis and induced ferroptosis via directly targeting calpain-2 in pancreatic cancer cells.
Tiliroside disrupted iron homeostasis and induced ferroptosis via directly targeting calpain-2 in pancreatic cancer cells.
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我们发现 TIL 是 CAPN2 的一种强效生物活性抑制剂，也是一种天然来源的抗 PC 候选物。这些发现还凸显了 CAPN2 作为 PC 治疗潜在靶点的价值。
银椴苷（TIL）是一种存在于多种食用植物中的黄酮类化合物。这些膳食植物被广泛用作食物和药物，用于治疗多种疾病。然而，TIL 对胰腺癌（PC）的作用及其潜在机制尚不清楚。
本研究旨在揭示 TIL 的抗 PC 作用并阐明其机制。
在体外和体内研究了 TIL 对 PC 生长的抑制作用。采用流式细胞术、透射电子显微镜、免疫荧光、生化分析、RT-qPCR、基因消融和 western blotting 评估铁死亡、自噬和铁调控。此外，结合 RNA 测序 (RNA-seq)、生物分子层干涉测量法 (BLI) 和分子模拟分析来鉴定 TIL 分子靶点。通过 PC 组织芯片上的免疫组织化学 (IHC) 确定了 Calpain-2 (CAPN2) 的临床病理学意义。
在此，我们表明TIL是一种有效的抗PC药物。CAPN2参与TIL诱导的PC细胞中不稳定铁池（LIP）升高。TIL直接结合并抑制CAPN2活性，导致PC细胞中AKT失活以及葡萄糖转运体（GLUT1和GLUT3）表达降低。因此，TIL损害ATP和NADPH生成，诱导自噬和ROS产生。TIL诱导的ROS积累与LIP铁结合引起Fenton反应，导致脂质过氧化。同时，TIL诱导的游离铁离子减少促进铁蛋白的自噬降解，以调节细胞铁稳态，这进一步加剧了PC细胞的铁死亡。作为这些体外发现的延伸，我们的小鼠异种移植研究显示，TIL抑制PANC-1细胞生长。此外，我们表明CAPN2表达水平与PC患者的临床预后相关。
Tiliroside (TIL) is a flavonoid compound that exists in a variety of edible plants. These dietary plants are widely used as food and medicine to treat various diseases. However, the effect of TIL on pancreatic cancer (PC) and its underlying mechanisms are unclear.
This study aims to reveal the anti-PC effect of TIL and clarify its mechanism.
The inhibitory effects of TIL on PC growth were studied both in vitro and in vivo. Flow cytometry, transmission electron microscopy, immunofluorescence, biochemical analyses, RT-qPCR, genetic ablation, and western blotting were employed to evaluate ferroptosis, autophagy, and iron regulation. Additionally, RNA sequencing (RNA-seq), biomolecular layer interferometry (BLI), and molecular simulation analysis were combined to identify TIL molecular targets. The clinicopathological significance of Calpain-2 (CAPN2) was determined through immunohistochemistry (IHC) on a PC tissue microarray.
Herein, we showed that TIL was an effective anti-PC drug. CAPN2 was involved in the TIL - induced elevation of the labile iron pool (LIP) in PC cells. TIL directly bound to and inhibited CAPN2 activity, resulting in AKT deactivation and decreased expression of glucose transporters (GLUT1 and GLUT3) in PC cells. Consequently, TIL impaired ATP and NADPH generation, inducing autophagy and ROS production. The accumulation of TIL-induced ROS combined with LIP iron causes the Fenton reaction, leading to lipid peroxidation. Meanwhile, TIL-induced reduction of free iron ions promoted autophagic degradation of ferritin to regulate cellular iron homeostasis, which further exacerbated the death of PC cells by ferroptosis. As an extension of these in vitro findings, our murine xenograft study showed that TIL inhibited the growth of PANC-1 cells. Additionally, we showed that CAPN2 expression levels were related to clinical prognoses in PC patients.
We identify TIL as a potent bioactive inhibitor of CAPN2 and an anti-PC candidate of natural origin. These findings also highlight CAPN2 as a potential target for PC treatment.
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