Gray Institute for Radiation Oncology and Biology, ORCRB, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.
Mol Cancer Res. 2011 Mar;9(3):249-58. doi: 10.1158/1541-7786.MCR-11-0021. Epub 2011 Feb 4.
TNF-related apoptosis-inducing ligand (TRAIL) is a current focus for the development of new cancer therapies, because of its selective induction of apoptosis in cancer cells. TRAIL has previously been shown to be important for tumor cell clearance from the liver; however, many cancer cell lines show some resistance toward TRAIL, posing a problem for the future use of TRAIL therapies. In this study, we show that interfering with a cell's ability to attach and spread onto a matrix can sensitize tumor cells to TRAIL-induced apoptosis in vitro. We targeted different members of the integrin signaling pathway using siRNA or inhibitors, including β-integrins, talin, Src, and downstream survival pathways PI3K and MAPK. Targeting any of these molecules could sensitize both MDA-MB-231 human breast cancer cells and TRAIL-resistant 1205Lu melanoma cells to TRAIL-induced apoptosis in vitro. Transcriptionally targeting the cytoskeleton, using myocardin-related transcription factor depletion to disrupt the transcription of cytoskeletal proteins, also caused TRAIL sensitization in MDA-MB-231 cells. We showed that this sensitivity to TRAIL correlated with increased activation of the intrinsic pathway of apoptosis. Manipulation of cell spreading therefore presents a potential method by which disseminated tumor cells could be sensitized to TRAIL therapies in vivo.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是开发新癌症疗法的当前重点，因为它能选择性诱导癌细胞凋亡。TRAIL 先前被证明对肝脏中肿瘤细胞的清除很重要；然而，许多癌细胞系对 TRAIL 表现出一定的抗性，这对未来 TRAIL 疗法的应用构成了问题。在这项研究中，我们表明，干扰细胞附着和在基质上扩散的能力可以使肿瘤细胞对 TRAIL 诱导的细胞凋亡敏感。我们使用 siRNA 或抑制剂靶向整合素信号通路的不同成员，包括β整合素、talin、Src 和下游的生存途径 PI3K 和 MAPK。靶向这些分子中的任何一个都可以使 MDA-MB-231 人乳腺癌细胞和 TRAIL 耐药的 1205Lu 黑色素瘤细胞对体外 TRAIL 诱导的细胞凋亡敏感。使用心肌营养素相关转录因子耗竭转录来破坏细胞骨架蛋白的转录，从转录上靶向细胞骨架，也会导致 MDA-MB-231 细胞对 TRAIL 敏感。我们表明，这种对 TRAIL 的敏感性与内在凋亡途径的激活增加相关。因此，细胞扩散的操纵提供了一种使体内播散的肿瘤细胞对 TRAIL 疗法敏感的潜在方法。
