文章：

TGF-β1和GRP78的联合下调通过重塑细胞表面CD44-GRP78-IGF-1R信号通路，介导索拉非尼获得性耐药的逆转

Combined downregulation of TGF-β1 and GRP78 is responsible for overcoming acquired sorafenib resistance, which is initiated by rewiring the cell surface CD44-GRP78-IGF-1R signaling circuit 

原文发布日期：2025-07-09 

英文摘要：

Previously, we showed that the downregulation of both HSP27 and TGF-β1 decreased the survival of various tumor types. However, we found that HSP27/TGF-β1 downregulation was less effective in acquired sorafenib-resistant HCC cell lines. As an alternative to HSP27/TGF-β1 downregulation to induce acute cell death in sorafenib-resistant cancer, we substituted shGRP78 for shHSP27 as a complement to shTGF-β1. The combination of shTGF-β1/shGRP78 was shown to overcome sorafenib resistance in HCC cell lines. Notably, both GRP78 and CD44 accumulate at the cell surface during sorafenib treatment and are accompanied by IRE1α activation; this effect is responsible for triggering and maintaining sorafenib resistance. These results revealed that sorafenib-induced acquired resistance in cancer cells is the result of receptor tyrosine kinase (RTK) feedback activation via the CD44-linked GRP78 signaling pathway with efficient rewiring of the GRP78-IGF1R-PI3K-Akt signaling cascade, which provides strong survival potential as well as a continuous positive feedback loop, resulting in sustained strong sorafenib resistance. In summary, CD44-GRP78 functions as both a sensor of sorafenib-induced ER stress and a mediator of sorafenib resistance. 

摘要翻译：

此前，我们发现HSP27和TGF-β1的下调会降低多种肿瘤类型的存活率。然而，在获得性索拉非尼耐药性HCC细胞系中，HSP27/TGF-β1下调的抑制作用较弱。为替代HSP27/TGF-β1下调策略以诱导索拉非尼耐药癌细胞的急性死亡，我们采用shGRP78替代shHSP27，与shTGF-β1形成联合方案。shTGF-β1/shGRP78联合应用被证明可克服HCC细胞系的索拉非尼耐药性。值得注意的是，在索拉非尼治疗期间，GRP78和CD44会在细胞表面聚集，并伴随IRE1α激活——这一效应是触发和维持索拉非尼耐药的关键机制。研究结果表明，索拉非尼诱导的癌细胞获得性耐药是通过CD44关联的GRP78信号通路实现受体酪氨酸激酶（RTK）反馈激活的结果：该通路有效重构了GRP78-IGF1R-PI3K-Akt信号级联，不仅提供强大的生存潜能，还形成持续的正反馈循环，最终导致稳定且强烈的索拉非尼耐药。综上所述，CD44-GRP78既能感知索拉非尼诱导的内质网应激，又是索拉非尼耐药的重要介质。

原文链接：

Combined downregulation of TGF-β1 and GRP78 is responsible for overcoming acquired sorafenib resistance, which is initiated by rewiring the cell surface CD44-GRP78-IGF-1R signaling circuit