Implications of aging and the endoplasmic reticulum unfolded protein response on the molecular modality of breast cancer

Abstract

The endoplasmic reticulum (ER) is an important subcellular organelle that is involved in numerous activities required to achieve and maintain functional proteins in addition to its role in the biosynthesis of lipids and as a repository of intracellular Ca2+. The inability of the ER to cope with protein folding beyond its capacity causes disturbances that evoke ER stress. Cells possess molecular mechanisms aimed at clearing unwanted cargo from the ER lumen as an adaptive response, but failing to do so navigates the system towards cell death. This systemic approach is called the unfolded protein response. Aging insults cells through various perturbations in homeostasis that involve curtailing ER function by mitigating the expression of its resident chaperones and enzymes. Here the unfolded protein response (UPR) cannot protect the cell due to the weakening of its protective arm, which exacerbates imbalanced homeostasis. Aging predisposed breast malignancy activates the UPR, but tumor cells maneuver the mechanistic details of the UPR, favoring tumorigenesis and thereby eliciting a treacherous condition. Tumor cells exploit UPR pathways via crosstalk involving various signaling cascades that usher tumor cells to immortality. This review aims to present a collection of data that can delineate the missing links of molecular signatures between aging and breast cancer.

Autophagy Plays a Critical Role in Insulin Resistance- Mediated Chemoresistance in Hepatocellular Carcinoma Cells by Regulating the ER Stress

“…Moreover, we evaluated the markers of ER stress including Glucose regulated protein 78 (GRP78), phosphorylation-protein kinase-like endoplasmic reticulum kinase (p-PERK)/ protein kinase-like endoplasmic reticulum kinase (PERK) and X-box binding protein 1 (XBP-1) 22 following treatment with RAPA and 3-MA respectively. The extent of down-regulation of GRP78 (35.6%), p-PERK/PERK (33.0%) and XBP-1(46.0%) in HepG2/IR cells were significantly greater than that in HepG2 cells under RAPA treatment (Figure 4 B).…”

Hsp90 inhibitors as senolytic drugs to extend healthy aging

“…During aging, a decline in the expression and activity of key ER molecular chaperones compromise proper protein folding and the adaptive response of the UPR [94,95]. Grp94, glucose regulated protein 78 (Grp78; also known as Immunoglobulin Binding protein -BiP), the lectins, calnexin and calreticulin, and the thiol-disulfide oxidoreductases, protein disulfide isomerase (PDI) and ERp57 are some of the major folding sensors and chaperones in the ER that diminish during the aging process [95][96][97][98]. In addition to their reduced expression levels, those chaperones are progressively oxidized with age.…”

A non-canonical arm of UPRER mediates longevity through ER remodeling and lipophagy

“…Although it is assumed that ER integrity and function breaks down with age, relatively little is understood about the mechanisms governing this process, especially in organismal models of extended longevity (Gordon, 1971;Minakshi et al, 2017;Palay and Palade, 1955). Here, we visualized the ER during various stages of adulthood in C. elegans using an mCherry::HDEL fusion protein that localizes to the ER lumen.…”