Estrogen-Induced Apoptosis in Breast Cancers Is Phenocopied by Blocking Dephosphorylation of Eukaryotic Initiation Factor 2 Alpha (eIF2α) Protein
Abstract
Approximately 30% of aromatase-inhibitor–resistant, estrogen receptor–positive patients with breast cancer benefit from treatment with estrogen. This enigmatic estrogen action is not well understood and how it occurs remains elusive. Studies indicate that the unfolded protein response and apoptosis pathways play important roles in mediating estrogen-triggered apoptosis. Using MCF7:5C cells, which mimic aromatase inhibitor resistance, and are hypersensitive to estrogen as evident by induction of apoptosis, we define increased global protein translational load as the trigger for estrogen-induced apoptosis. The protein kinase RNA-like endoplasmic reticulum kinase pathway was activated followed by increased phosphorylation of eukaryotic initiation factor-2 alpha (eIF2α). These actions block global protein translation but preferentially allow high expression of specific transcription factors, such as activating transcription factor 4 and C/EBP homologous protein that facilitate apoptosis. Notably, we recapitulated this phenotype of MCF7:5C in two other endocrine therapy–resistant cell lines (MCF7/LCC9 and T47D:A18/4-OHT) by increasing the levels of phospho-eIF2α using salubrinal to pharmacologically inhibit the enzymes responsible for dephosphorylation of eIF2α, GADD34, and CReP. RNAi-mediated ablation of these genes induced apoptosis that used the same signaling as salubrinal treatment. Moreover, combining 4-hydroxy tamoxifen with salubrinal enhanced apoptotic potency.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2019
- Source ID
- 10.1158/1541-7786.mcr-18-0481
Entities
People
- Catherine M Sevigny
- Poulomi Bhattacharya
- Robert Clarke
- Surojeet Sengupta
- V. Craig Jordan
Organizations
- Georgetown University
- National Institutes of Health
- United States Department of Defense
- United States Public Health Service
- University of Texas at Austin