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首页> 外文期刊>Biochemical Pharmacology >Sorafenib suppresses TGF-beta responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-beta receptors: Implications in development of effective adjunctive therapy for hepatocellular carcinoma
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Sorafenib suppresses TGF-beta responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-beta receptors: Implications in development of effective adjunctive therapy for hepatocellular carcinoma

机译：Sorafenib通过诱导Caveolae /脂质筏介导的细胞表面II TGF-β受体的内化/降解来抑制TGF-β反应：对肝细胞癌有效辅助治疗的影响

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摘要

Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-beta signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-beta promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-beta-induced EMT. It improves survival of patients but HCC later develops resistance and relapses. The underlying mechanism of resistance is unknown. Understanding of the molecular mechanism of sorafenib inhibition of TGF-beta-induced signalling or responses in HCC may lead to development of adjunctive effective therapy for HCC. In this study, we demonstrate that sorafenib suppresses TGF-beta responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-beta receptors (T beta RII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface T beta II is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface T beta II localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-beta signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface T beta R-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-beta receptor kinase inhibitors (e.g., LY2157299) or TGF-beta peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC.
机译：Sorafenib是唯一批准用于治疗晚期肝细胞癌（HCC）和其他恶性肿瘤药物的FDA批准的药物。研究表明，TGF-β信令与HCC中的肿瘤进展相关。通过诱导上皮 - 间充质转换（EMT）来促进肿瘤生长和恶性肿瘤。索拉非尼被认为通过抑制TGF-Beta诱导的EMT来拮抗肿瘤进展。它改善了患者的存活，但HCC后来显影了抗性并复发。抵抗的潜在机制是未知的。理解Sorafenib对HCC中TGF-β诱导的信号传导或反应的抑制的分子机制可能导致HCC的辅助有效治疗的发展。在这项研究中，我们证明索拉非尼抑制了肝癌细胞，肝细胞和动物肝脏的TGF-β反应性，主要是通过在Caveolae /脂质筏和非脂质中局部化的细胞表面II TGF-β受体（TβRII）下调通过Caveolae /脂质筏介导的内化和降解筏微摩擦。此外，通过用Caveolae破坏器或溶酶体抑制剂同时处理，通过同时处理来防止SoraFenib诱导的细胞表面TβII的下调和降解。另一方面，索拉非尼仅在肝星状细胞中局部地下调位于Caveolae /脂质筏中的细胞表面TβII，但未在非脂质筏微摩中局部化。这些结果表明，Sorafenib主要通过诱导Caveolae /脂质筏介导的内化和靶细胞中细胞表面TβR-II的降解来抑制TGF-β发信号。它们还可以暗示用促进Caveolae /脂质筏，TGF-β受体激酶抑制剂（例如，Ly2157299）或TGF-β肽拮抗剂（通过肝脏靶向递送）的药物治疗可被认为是Sorafenib的有效辅助治疗对于HCC。

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