E-Cadherin Couples Death Receptors to the Cytoskeleton to Regulate Apoptosis

Min Lu, Scot Marsters, Xiaofen Ye, Elizabeth Luis, Lino Gonzalez, and Avi Ashkenazi,

Mol Cell. (2014)54, 987-98

Speaker: Wei-Sheng Chen (陳維昇)                            Time: 15:10~16:00, May. 27, 2015

Commentator: Dr. Chi-Wu Chiang (蔣輯武 老師)  Place: Room 601

Abstract:

The epithelial-mesenchymal transition (EMT) is a process by which cells lose epithelial polarity and gain a migratory, invasive mesenchymal phenotype. In previous study, malignant epithelialcancer cells that undergo EMT tend to promote metastasis by reducing apoptotic sensitivity and resisting to chemotherapies, targeted therapies, but the mechanisms remain unclear [1,2]. Apoptosis can be triggered by cell-extrinsic or cell-intrinsic stimulation [3]. The cell-extrinsic pathway is initiated by Apo2L/TRAIL proteins, the tumor necrosis factor (TNF) ligand family, to engagement with surface death receptors DR4 (TRAIL-R1) and/or DR5 (TRAIL-R2). In this paper, the authors treated epithelial cancer cell line (NCI-H58) with transforming growth factor β (TGF-β), and Apo2L to explore the mechanisms of EMT and apoptosis. The results demonstrated that EMT attenuated apoptosis signaling by Apo2L/TRAIL. Moreover, loss of cell adhesion protein E-cadherin contributed to this phenomenon, whereas homotypic E-cadherin engagement promoted apoptotic signaling via DR4/DR5. Furthermore, the authors set up in vitro model system to demonstrate that E-cadherin directly and selectively interacts with ligated DR4 and DR5, but not Fas receptor. Taken together, E-cadherin coupling DR4 and DR5 via α-catenin to the actin cytoskeleton and thereby promoting efficient receptor clustering, death-inducing signaling complex (DISC) assembly, and caspase-8 activation. This study provides an important insight of the regulation between EMT and apoptosis. It has potential implications for epithelial biology and cancer therapy.

References:

1.         Yang. et al. (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 14, 818-29.

2.         Singh. et al. (2010). EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 29, 4741-4751.

3.         Danial. et al. (2004). Cell death: critical control points. Cell. 116, 205-19.