TY - JOUR
T1 - Disulfide bond-disrupting agents activate the tumor necrosis family-related apoptosis-inducing ligand/death receptor 5 pathway
AU - Wang, Mengxiong
AU - Law, Mary E.
AU - Davis, Bradley J.
AU - Yaaghubi, Elham
AU - Ghilardi, Amanda F.
AU - Ferreira, Renan B.
AU - Chiang, Chi Wu
AU - Guryanova, Olga A.
AU - Kopinke, Daniel
AU - Heldermon, Coy D.
AU - Castellano, Ronald K.
AU - Law, Brian K.
N1 - Funding Information:
These studies were supported in part by grants from the Florida Breast Cancer Foundation (B.L. and R.C.), the Ocala Royal Dames for Cancer Research (B.L.), the Florida Department of Health Bankhead-Coley Program (4BF03, B.L.), the Collaboration of Scientists for Critical Research in Biomedicine (CSCRB, Inc., B. L.), and a UF-Health Cancer Center pilot project award (B.L., R.C., and C.H.). This work was supported in part by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award Nos. W81XWH-15-1-0199 (B.L.) and W81XWH-15-1-0200 (R.C.). RBF is grateful to the University of Florida for a Graduate School Fellowship. Finally, we thank breast cancer research advocate Mrs. Jeri Francoeur for her advice and support.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Disulfide bond-disrupting agents (DDAs) are a new chemical class of agents recently shown to have activity against breast tumors in animal models. Blockade of tumor growth is associated with downregulation of EGFR, HER2, and HER3 and reduced Akt phosphorylation, as well as the induction of endoplasmic reticulum stress. However, it is not known how DDAs trigger cancer cell death without affecting nontransformed cells. As demonstrated here, DDAs are the first compounds identified that upregulate the TRAIL receptor DR5 through transcriptional and post-transcriptional mechanisms to activate the extrinsic cell death pathway. At the protein level, DDAs alter DR5 disulfide bonding to increase steady-state DR5 levels and oligomerization, leading to downstream caspase 8 and 3 activation. DDAs and TRAIL synergize to kill cancer cells and are cytotoxic to HER2+ cancer cells with acquired resistance to the EGFR/HER2 tyrosine kinase inhibitor Lapatinib. Investigation of the mechanisms responsible for DDA selectivity for cancer cells reveals that DDA-induced upregulation of DR5 is enhanced in the context of EGFR overexpression. DDA-induced cytotoxicity is strongly amplified by MYC overexpression. This is consistent with the known potentiation of TRAIL-mediated cell death by MYC. Together, the results demonstrate selective DDA lethality against oncogene-transformed cells, DDA-mediated DR5 upregulation, and protein stabilization, and that DDAs have activity against drug-resistant cancer cells. Our results indicate that DDAs are unique in causing DR5 accumulation and oligomerization and inducing downstream caspase activation and cancer cell death through mechanisms involving altered DR5 disulfide bonding. DDAs thus represent a new therapeutic approach to cancer therapy.
AB - Disulfide bond-disrupting agents (DDAs) are a new chemical class of agents recently shown to have activity against breast tumors in animal models. Blockade of tumor growth is associated with downregulation of EGFR, HER2, and HER3 and reduced Akt phosphorylation, as well as the induction of endoplasmic reticulum stress. However, it is not known how DDAs trigger cancer cell death without affecting nontransformed cells. As demonstrated here, DDAs are the first compounds identified that upregulate the TRAIL receptor DR5 through transcriptional and post-transcriptional mechanisms to activate the extrinsic cell death pathway. At the protein level, DDAs alter DR5 disulfide bonding to increase steady-state DR5 levels and oligomerization, leading to downstream caspase 8 and 3 activation. DDAs and TRAIL synergize to kill cancer cells and are cytotoxic to HER2+ cancer cells with acquired resistance to the EGFR/HER2 tyrosine kinase inhibitor Lapatinib. Investigation of the mechanisms responsible for DDA selectivity for cancer cells reveals that DDA-induced upregulation of DR5 is enhanced in the context of EGFR overexpression. DDA-induced cytotoxicity is strongly amplified by MYC overexpression. This is consistent with the known potentiation of TRAIL-mediated cell death by MYC. Together, the results demonstrate selective DDA lethality against oncogene-transformed cells, DDA-mediated DR5 upregulation, and protein stabilization, and that DDAs have activity against drug-resistant cancer cells. Our results indicate that DDAs are unique in causing DR5 accumulation and oligomerization and inducing downstream caspase activation and cancer cell death through mechanisms involving altered DR5 disulfide bonding. DDAs thus represent a new therapeutic approach to cancer therapy.
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U2 - 10.1038/s41420-019-0228-9
DO - 10.1038/s41420-019-0228-9
M3 - Article
AN - SCOPUS:85076355036
VL - 5
JO - Cell Death Discovery
JF - Cell Death Discovery
SN - 2058-7716
IS - 1
M1 - 153
ER -