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

Chen Qi, Xin Wang, Zhirong Shen, She Chen, Hong Yu, Noelle S Williams, Gelin Wang

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)544-555
Number of pages12
JournalCell Research
Volume28
Issue number5
DOIs
StatePublished - May 1 2018

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Receptors, Tumor Necrosis Factor, Member 25
Apoptosis
Antimitotic Agents
Neoplasms
Tumor Necrosis Factor Ligand Superfamily Member 15
Cell Death
Death Domain Receptor Signaling Adaptor Proteins
Spindle Apparatus
Vinblastine
Caspase 8
Poisons
Paclitaxel
Cell Cycle Checkpoints
Lysosomes
Heterografts
Pharmaceutical Preparations
Biomarkers
Cell Line

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Anti-mitotic chemotherapeutics promote apoptosis through TL1A-activated death receptor 3 in cancer cells. / Qi, Chen; Wang, Xin; Shen, Zhirong; Chen, She; Yu, Hong; Williams, Noelle S; Wang, Gelin.

In: Cell Research, Vol. 28, No. 5, 01.05.2018, p. 544-555.

Research output: Contribution to journalArticle

Qi, Chen ; Wang, Xin ; Shen, Zhirong ; Chen, She ; Yu, Hong ; Williams, Noelle S ; Wang, Gelin. / Anti-mitotic chemotherapeutics promote apoptosis through TL1A-activated death receptor 3 in cancer cells. In: Cell Research. 2018 ; Vol. 28, No. 5. pp. 544-555.
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