Abstract
The unfolded protein response (UPR) is an ancient stress response that enables a cell to manage the energetic stress that accompanies protein folding. There has been a significant recent increase in our understanding of the UPR, how it integrates physiological processes within cells, and how this integration can affect cancer cells and cell fate decisions. Recent publications have highlighted the role of UPR signaling components on mediating various cell survival pathways, cellular metabolism and bioenergenics, and autophagy. We address the role of UPR on mediating endocrine therapy resistance and estrogen receptor-positive breast cancer cell survival.
Highlights
Reviewed by: Ruchi Chaube, Case Western Reserve University, USA Luca Ulianich, Consiglio Nazionale delle Ricerche, Italy
We previously showed that the selective estrogen receptor downregulator (SERD) including tamoxifen (TAM) or fulvestrant (ICI) stimulates unfolded protein response (UPR) signaling in both antiestrogen sensitive and resistant breast cancer cell lines
We showed that ICI increased cytoplasmic aggregation of ERα, and that endocrine resistant LCC9 cells have elevated basal levels of cytoplasmic ERα, when compared with their therapy sensitive parental cells, likely explaining the increased UPR signaling observed in these cell lines [53]
Summary
The unfolded protein response (UPR) is an endoplasmic reticulum stress pathway, activated when unfolded or misfolded proteins accumulate within the endoplasmic reticulum lumen. The master regulator of UPR signaling, glucose-regulated protein 78 (HSPA5; GRP78), activates the UPR as a consequence of its release from the three UPR signaling controllers, PKR-like endoplasmic reticulum kinase (EIF2AK3; PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (ERN1; IRE1). Release of IRE1 from GRP78 enables IRE1 to oligermize and autophosphorylate This activation of IRE1 enables its unconventional cytoplasmic splicing of X-box binding protein 1 (XBP1); the endonuclease activity of IRE1 removes a 26-base pair intron in XBP1 to produce its transcriptionally active form (XBP1-spliced, XBP1-S; Figure 2). XBP1-S increases the transcription of other protein chaperones, endoplasmic reticulum-associated protein degradation (ERAD), and inflammatory genes such as IL-6. Initial activation of UPR signaling is usually pro-survival, resulting in a reduced rate of protein translation and increased protein
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