Abstract
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/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.
Highlights
The most distinguishing hallmark of cancer is uncontrolled cell growth and division
To delineate death receptor 3 (DR3) and Bcl[2] family proteins in cell death triggered by anti-mitotics, we examined the regulation of Mcl[1] and Bcl-xL in response to diazonamide in Mad[2] or DR3 knockdown cells
The signaling pathways that activate cell death induced by antimitotic chemotherapeutics are of great interest
Summary
The most distinguishing hallmark of cancer is uncontrolled cell growth and division. Chemical and biological agents that antagonize these features are most commonly used in the clinical treatment of cancer. It was found that diazonamide caused mitotic spindle dysfunction, which could primarily contribute to its killing effects on cancer cells and xenografted tumor.[7,8] Diazonamide functions differently from other antimitotics when administered to eliminate xenograft tumors It preserves the microtubule network in non-dividing cells and in primary neurons; does not cause any body-weight loss, any change in overall physical appearance, or any evidence of neutropenia; and functions as effectively as taxanes and vinca alkaloids. Antimitotic agents cause cells to arrest in the metaphase for some period of time prior to an aberrant exit from mitosis into a state called ‘mitotic catastrophe’ This activates a death pathway leading to cancer cell death, a feature contributing to the clinical response and prognoses of those drugs. Scale bars represent 100 μm. c Cell viability was determined after 48 h treatment of 100 nM diazonamide or taxol. d Mad[2] knockdown efficiency was analyzed by western blotting with an anti-Mad[2] antibody and normalized by Actin
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