Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, ROC.
Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 81326, Taiwan, ROC.
Biochem Pharmacol. 2018 Aug;154:39-53. doi: 10.1016/j.bcp.2018.04.014. Epub 2018 Apr 18.
Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-β signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-β promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-β-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-β-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-β responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-β receptors (TβRII) 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 TβRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TβRII localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-β signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface TβR-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-β receptor kinase inhibitors (e.g., LY2157299) or TGF-β peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC.
索拉非尼是唯一被 FDA 批准用于治疗晚期肝细胞癌（HCC）和其他恶性肿瘤的药物。研究表明，TGF-β信号与 HCC 中的肿瘤进展有关。自分泌和旁分泌 TGF-β 通过诱导上皮-间充质转化（EMT）促进肿瘤生长和恶性转化。索拉非尼被认为通过抑制 TGF-β诱导的 EMT 来拮抗肿瘤进展。它改善了患者的生存率，但 HCC 后来会产生耐药性并复发。耐药的潜在机制尚不清楚。了解索拉非尼抑制 HCC 中 TGF-β 诱导的信号或反应的分子机制，可能会导致开发 HCC 的辅助有效治疗方法。在这项研究中，我们证明索拉非尼主要通过下调质膜 II 型 TGF-β受体（TβRII），从而抑制肝癌细胞、肝细胞和动物肝脏中的 TGF-β反应性，下调的 TβRII 位于质膜小窝/脂筏和非脂筏微区室中，通过质膜小窝/脂筏介导的内化和降解。此外，用质膜小窝破坏剂或溶酶体抑制剂同时处理可以防止索拉非尼诱导的细胞表面 TβRII 下调和降解。另一方面，索拉非尼仅下调位于质膜小窝/脂筏中的细胞表面 TβRII，但不下调位于肝星状细胞中非脂筏微区室中的细胞表面 TβRII。这些结果表明，索拉非尼通过诱导靶细胞中质膜小窝/脂筏介导的细胞表面 TβR-II 内化和降解，主要抑制 TGF-β 信号。它们还可能暗示，用促进质膜小窝/脂筏形成的药物（例如 LY2157299）、TGF-β受体激酶抑制剂或 TGF-β肽拮抗剂（通过肝靶向递送来治疗）与索拉非尼联合治疗 HCC 可能是一种有效的辅助治疗方法。
