Gelin WANG publishes “Anti-mitotic Chemotherapeutics Promote Apoptosis through TL1A-activated Death Receptor 3 in Cancer Cells” in Cell Research
Mar 05, 2018
The commonly used anti-mitotic 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 of how 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 and caspase-8-containing death-inducing signaling complex (DISC), which subsequently activates apoptosis in cells that express DR3. Expression of DR3 and TL1A correspond to the apoptotic response of human tumor xenograft models and human cancer cell lines to anti-mitotic drugs, providing further evidence that they kill cancer cells through DR3/TL1A-mediated pathway. These results suggest TL1A and DR3 may hold promise to be used as predicting biomarkers for clinical response to anti-mitotic therapeutics.
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