Oncologic Pathology Group, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova-Department de Ciencias Mediques Basiques, Univeristat de Lleida, Institut de Recerca Biomèdica de Lleida, IRBLleida, Spain.
Eur J Cancer. 2010 Mar;46(4):836-50. doi: 10.1016/j.ejca.2009.12.025. Epub 2010 Jan 12.
Sorafenib induces apoptosis and enhances Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-induced cell killing of tumoural cells. We have investigated the effects of the multikinase inhibitor Sorafenib alone or in combination with TRAIL and agonistic Fas antibodies on endometrial carcinoma cells. We have also focused on the search of the differential molecular mechanisms by which Sorafenib induces cell death and the ones involved in sensitisation to TRAIL. In the present study, we show that Sorafenib induces apoptosis of both endometrial cancer cell lines and human primary cultures and sensitises these cells to TRAIL and agonistic Fas antibodies (aFas)-induced apoptosis. However, Raf/MEK/ERK inhibition by Sorafenib was not responsible for Sorafenib cell death or TRAIL sensitisation of endometrial cancer cells. Sorafenib treatment correlated with a downregulation of both FLICE-Inhibitory Protein (FLIP) and myeloid cell leukaemia-1 (Mcl-1), caused by a proteasomal degradation of both proteins. We evaluated the contribution of FLIP and Mcl-1 downregulation in apoptosis triggered by Sorafenib alone or Sorafenib plus TRAIL. Interestingly, cell death caused by Sorafenib was mediated by downregulation of Mcl-1, but not by FLIP. In contrast, we found that Sorafenib sensitisation of endometrial carcinoma cells to TRAIL- and Fas-induced apoptosis was dependent on FLIP but not on Mcl-1 downregulation. Altogether, we discern the dual mechanisms by which Sorafenib causes cell death from those involved in death receptor sensitisation.
索拉非尼诱导肿瘤细胞凋亡，并增强肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的细胞杀伤作用。我们研究了多激酶抑制剂索拉非尼单独或与 TRAIL 和激动型 Fas 抗体联合对子宫内膜癌细胞的影响。我们还专注于寻找索拉非尼诱导细胞死亡的差异分子机制，以及参与 TRAIL 敏感性的机制。在本研究中，我们表明索拉非尼诱导两种子宫内膜癌细胞系和人原代培养物的凋亡，并使这些细胞对 TRAIL 和激动型 Fas 抗体（aFas）诱导的凋亡敏感。然而，索拉非尼对 Raf/MEK/ERK 的抑制作用并不是导致索拉非尼引起的细胞死亡或 TRAIL 对子宫内膜癌细胞的敏感性的原因。索拉非尼治疗与两种蛋白质的蛋白酶体降解相关，导致 FLICE 抑制蛋白（FLIP）和髓样细胞白血病-1（Mcl-1）的下调。我们评估了 FLIP 和 Mcl-1 下调在索拉非尼单独或索拉非尼加 TRAIL 引起的细胞凋亡中的作用。有趣的是，索拉非尼引起的细胞死亡是由 Mcl-1 的下调介导的，而不是由 FLIP 介导的。相反，我们发现索拉非尼对子宫内膜癌细胞对 TRAIL 和 Fas 诱导的凋亡的敏感性依赖于 FLIP，但不依赖于 Mcl-1 的下调。总之，我们发现了索拉非尼引起细胞死亡的双重机制，以及参与死亡受体敏感性的机制。
