Disulfide bond-disrupting agents activate the tumor necrosis family-related apoptosis-inducing ligand/death receptor 5 pathway.

摘要: Disulfide bond-disrupting agents (DDAs) are a new chemical class of recently shown to have activity against breast tumors in animal models. Blockade tumor growth is associated with downregulation EGFR, HER2, and HER3 reduced Akt phosphorylation, as well the induction endoplasmic reticulum stress. However, it not known how DDAs trigger cancer cell death without affecting nontransformed cells. As demonstrated here, first compounds identified that upregulate TRAIL receptor DR5 through transcriptional post-transcriptional mechanisms activate extrinsic pathway. At protein level, alter disulfide bonding increase steady-state levels oligomerization, leading downstream caspase 8 3 activation. synergize kill cells cytotoxic HER2+ acquired resistance EGFR/HER2 tyrosine kinase inhibitor Lapatinib. Investigation responsible for DDA selectivity reveals DDA-induced upregulation enhanced context EGFR overexpression. cytotoxicity strongly amplified by MYC This consistent potentiation TRAIL-mediated MYC. Together, results demonstrate selective lethality oncogene-transformed cells, DDA-mediated upregulation, stabilization, drug-resistant Our indicate unique causing accumulation oligomerization inducing activation involving altered bonding. thus represent therapeutic approach therapy.