Anti-mitotic chemotherapeutics promote apoptosis through TL1A-activated death receptor 3 in cancer cells
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 FADD-containing 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/TL1 A-mediated pathway. These results suggest that TL1A and DR3 may hold promise to be used as biomarkers for predicting clinical response to antimitotic therapeutics.
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grant 53110000117 from Tsinghua University;grant 2P01 CA095471 from National Cancer Institute G.W. and N.W.. We thank Xiaodong Wang for his important scientific input, Patrick Harran for diazonamide reagents, Steven McKnight for critically reading the manuscript, Zhigao Wang for helpful discussion, Fenghe Du for technical assistance, Shugu
2018-08-28（万方平台首次上网日期，不代表论文的发表时间）
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544-555
