Anti-mitotic chemotherapeutics promote apoptosis through TL1A-activated death receptor 3 in cancer cells

作者：Qi, Chen; Wang, Xin; Shen, Zhirong; Chen, She; Yu, Hong; Williams, Noelle; Wang, Gelin^*

来源：Cell Research, 2018, 28(5): 544-555.

DOI：10.1038/s41422-018-0018-6

• SPINDLE ASSEMBLY CHECKPOINT
• T-CELL
• IDENTIFICATION
• MITOSIS
• AGENTS
• DR3
• SENSITIVITY
• TUBULIN
• FAMILY
• TWEAK

The commonly used antimitotic chemotherapeutic agents such as taxol and vinblastine arrest cell cycle progression by disrupting mitotic spindles, and cause cancer cells to undergo apoptosis through 'mitotic catastrophe'. The molecular mechanisms by which these drugs induce apoptosis and their relevance to clinical efficacy are not known. Facilitated by a new spindle poison diazonamide, we found that apoptosis induced by these agents requires death receptor 3 (DR3). Mitotic arrest by these agents induces lysosome-dependent secretion of the DR3 ligand, TL1A. Engagement of TL1A with DR3 stimulates the formation of FADDcontaining and caspase-8-containing death-inducing signaling complex (DISC), which subsequently activates apoptosis in cells that express DR3. Expression of DR3 and TL1A correlates with the apoptotic response of human tumor xenograft models and human cancer cell lines to antimitotic drugs, providing further evidence that these drugs kill cancer cells through the DR3/TL1A-mediated pathway. These results suggest that TL1A and DR3 may hold promise to be used as biomarkers for predicting clinical response to antimitotic therapeutics.

• 单位
  北京生命科学研究所; 清华大学