Details

Autor(en) / Beteiligte

• Gupta, Malavika
• Walters, Beth A
• Katsara, Olga
• Granados Blanco, Karol
• Geter, Phillip A
• Schneider, Robert J

Titel

eIF2Bδ blocks the integrated stress response and maintains eIF2B activity and cancer metastasis by overexpression in breast cancer stem cells

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2023-04, Vol.120 (15), p.e2207898120-e2207898120

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Breast cancer (BC) metastasis involves cancer stem cells (CSCs) and their regulation by micro-RNAs (miRs), but miR targeting of the translation machinery in CSCs is poorly explored. We therefore screened miR expression levels in a range of BC cell lines, comparing non-CSCs to CSCs, and focused on miRs that target translation and protein synthesis factors. We describe a unique translation regulatory axis enacted by reduced expression of miR-183 in breast CSCs, which we show targets the eIF2Bδ subunit of guanine nucleotide exchange factor eIF2B, a regulator of protein synthesis and the integrated stress response (ISR) pathway. We report that reduced expression of miR-183 greatly increases eIF2Bδ protein levels, preventing strong induction of the ISR and eIF2α phosphorylation, by preferential interaction with P-eIF2α. eIF2Bδ overexpression is essential for BC cell invasion, metastasis, maintenance of metastases, and breast CSC expansion in animal models. Increased expression of eIF2Bδ, a site of action of the drug ISRIB that also prevents ISR signaling, is essential for breast CSC maintenance and metastatic capacity.