Caveolin-1/EGFR/Src复合物调控胃癌对TRAIL耐药的机制研究

Gastric cancer is the most common digestive system neoplasm in China. The effect of current therapy is not satisfying. As a biological targeted drug, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has entered clinical trials. However, gastric cancer cells are insensitive to TRAIL. It has been reported that lipid rafts in cell membrane provide an important platform for regulating TRAIL sensitivity. Caveolin-1, located in caveolae, is an essential constituent molecule of lipid rafts. Our recent study has demonstrated that TRAIL-activated EGFR by promoting EGFR translocation into lipid rafts is the important reason for TRAIL resistance in gastric cancer cells. Our latest data has shown that Caveolin-1/EGFR/Src compound exists in TRAIL-resistant gastric cancer cells. When TRAIL triggers apoptosis, TRAIL also obviously enhances the quantity of the compound. However, whether the formation and change of the compound play a role in the resistance of gastric cancer cells to TRAIL is yet unknown. Our aim is to identify the mechanism of the formation and change of Caveolin-1/EGFR/Src compound, and the regulatory function of the compound to TRAIL sensitivity in gastric cancer cells. Our study provides a new insight to understand the mechanism of TRAIL resistance and a novel strategy for clinical application of TRAIL.

胃癌是我国常见的消化系统肿瘤，现有疗法的疗效不理想。肿瘤坏死因子相关凋亡诱导配体（TRAIL）作为生物靶向药物已进入临床试验，但胃癌对TRAIL不敏感。文献报告，位于细胞膜的脂筏是调控TRAIL敏感性的关键平台，而胞膜窖内的窖蛋白-1（caveolin-1）是脂筏的重要组成分子。我们的研究证实：①TRAIL通过促进EGFR向脂筏转位诱导EGFR的活化是胃癌对TRAIL耐药的重要原因。②在TRAIL耐药的胃癌细胞中，存在Caveolin-1/EGFR/Src复合物；TRAIL启动凋亡时能明显增加该复合物的含量。但是，该复合物的形成及变化在胃癌对TRAIL耐药中所起的作用不清楚。本研究的目的是明确TRAIL作用胃癌后，Caveolin-1/EGFR/Src复合物形成和变化机制，及其对TRAIL敏感性的调控作用。本研究为阐明胃癌对TRAIL的耐药机理以及TRAIL的临床应用提供新的策略。

胃癌是我国常见的消化系统恶性肿瘤。生物靶向药--肿瘤坏死因子相关凋亡诱导配体（TRAIL）已进入临床试验，但胃癌对TRAIL不敏感。位于细胞膜的脂筏是调控TRAIL敏感性的关键平台，而胞膜窖内的窖蛋白-1（caveolin-1）是脂筏的重要组成分子。我们的研究证实：①在TRAIL耐药的胃癌细胞中，TRAIL诱导了EGFR和Src进入富含caveolin-1的胞膜窖内，增加了Src与EGFR和caveolin-1的结合，并诱导了Src、caveolin-1、EGFR和下游信号的活化。②敲除Caveolin-1抑制了TRAIL诱导的EGFR和下游信号的活化，并提高TRAIL的敏感性。③抑制Src激酶的活性，减少了Src与EGFR和caveolin-1的结合，并抑制TRAIL诱导的caveolin-1、EGFR和下游信号的活化，提高了TRAIL的敏感性。④通过体内实验证实，Src抑制剂PP2能提高TRAIL治疗胃癌荷瘤小鼠的疗效。本研究明确了TRAIL作用胃癌后，caveolin-1/EGFR/Src的结合和变化机制，及其对TRAIL敏感性的调控作用。本研究为阐明胃癌对TRAIL的耐药机理以及TRAIL的临床应用提供新的策略。