Du Wanlu, Uslar Liubov, Sevala Sindhura, Shah Khalid
Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, United States of America.
PLoS One. 2014 Apr 18;9(4):e95490. doi: 10.1371/journal.pone.0095490. eCollection 2014.
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induced apoptosis specifically in tumor cells. However, with approximately half of all known tumor lines being resistant to TRAIL, the identification of TRAIL sensitizers and their mechanism of action become critical to broadly use TRAIL as a therapeutic agent. In this study, we explored whether c-Met protein contributes to TRAIL sensitivity. We found a direct correlation between the c-Met expression level and TRAIL resistance. We show that the knock down c-Met protein, but not inhibition, sensitized brain tumor cells to TRAIL-mediated apoptosis by interrupting the interaction between c-Met and TRAIL cognate death receptor (DR) 5. This interruption greatly induces the formation of death-inducing signaling complex (DISC) and subsequent downstream apoptosis signaling. Using intracranially implanted brain tumor cells and stem cell (SC) lines engineered with different combinations of fluorescent and bioluminescent proteins, we show that SC expressing a potent and secretable TRAIL (S-TRAIL) have a significant anti-tumor effect in mice bearing c-Met knock down of TRAIL-resistant brain tumors. To our best knowledge, this is the first study that demonstrates c-Met contributes to TRAIL sensitivity of brain tumor cells and has implications for developing effective therapies for brain tumor patients.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）可特异性诱导肿瘤细胞凋亡。然而，在所有已知的肿瘤细胞系中，约有一半对TRAIL耐药，因此，鉴定TRAIL增敏剂及其作用机制对于广泛应用TRAIL作为治疗药物至关重要。在本研究中，我们探讨了c-Met蛋白是否影响TRAIL敏感性。我们发现c-Met表达水平与TRAIL耐药性之间存在直接关联。我们发现，敲低c-Met蛋白而非抑制c-Met蛋白，可通过中断c-Met与TRAIL同源死亡受体（DR）5之间的相互作用，使脑肿瘤细胞对TRAIL介导的凋亡敏感。这种中断极大地诱导了死亡诱导信号复合物（DISC）的形成及随后的下游凋亡信号传导。利用颅内植入的脑肿瘤细胞以及用荧光蛋白和生物发光蛋白的不同组合构建的干细胞（SC）系，我们发现表达强效且可分泌的TRAIL（S-TRAIL）的SC对携带c-Met敲低的TRAIL耐药性脑肿瘤的小鼠具有显著的抗肿瘤作用。据我们所知，这是第一项证明c-Met影响脑肿瘤细胞对TRAIL敏感性的研究，对开发针对脑肿瘤患者的有效治疗方法具有重要意义。
