Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death

Mary E. Law, Elham Yaaghubi, Amanda F. Ghilardi, Bradley J. Davis, Renan B. Ferreira, Jin Koh, Sixue Chen, Sadie F. DePeter, Christopher M. Schilson, Chi Wu Chiang, Coy D. Heldermon, Peter Nørgaard, Ronald K. Castellano, Brian K. Law

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4 引文 斯高帕斯(Scopus)

摘要

Breast cancer mortality remains unacceptably high, indicating a need for safer and more effective therapeutic agents. Disulfide bond Disrupting Agents (DDAs) were previously identified as a novel class of anticancer compounds that selectively kill cancers that overexpress the Epidermal Growth Factor Receptor (EGFR) or its family member HER2. DDAs kill EGFR+ and HER2+ cancer cells via the parallel downregulation of EGFR, HER2, and HER3 and activation/oligomerization of Death Receptors 4 and 5 (DR4/5). However, the mechanisms by which DDAs mediate these effects are unknown. Affinity purification analyses employing biotinylated-DDAs reveal that the Protein Disulfide Isomerase (PDI) family members AGR2, PDIA1, and ERp44 are DDA target proteins. Further analyses demonstrate that shRNA-mediated knockdown of AGR2 and ERp44, or expression of ERp44 mutants, enhance basal DR5 oligomerization. DDA treatment of breast cancer cells disrupts PDIA1 and ERp44 mixed disulfide bonds with their client proteins. Together, the results herein reveal DDAs as the first small molecule, active site inhibitors of AGR2 and ERp44, and demonstrate roles for AGR2 and ERp44 in regulating the activity, stability, and localization of DR4 and DR5, and activation of Caspase 8.

原文English
文章編號215604
期刊Cancer Letters
534
DOIs
出版狀態Published - 2022 5月 28

All Science Journal Classification (ASJC) codes

  • 腫瘤科
  • 癌症研究

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