Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in ER, mitochondria, and mitochondria-associated ER membranes (MAMs). (IMAGE)

Compuscript Ltd

Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in ER, mitochondria, and mitochondria-associated ER membranes (MAMs).

Caption

(A) ER stress and UPR in physiology. During ER stress, the competitive binding of unfolded or misfolded proteins to immunoglobulin heavy chain binding protein (BiP) displaces it from inositol-requiring enzyme 1 (IRE1), protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6), leading to the activation of downstream signaling pathways. Mitochondrial fusion protein 2 (MFN2) directly interacts with PERK within the MAMs, acting as a tether. Under ER stress, IRE1 interacts with sigma-1 receptor (Sig-1R), promoting dimerization and facilitating Ca2+ transfer to the mitochondria through inositol 1,4,5-trisphosphate receptor (IP3R)-mediated mechanisms. (B) ER stress and therapy targets in colorectal cancer (CRC). ATPase family AAA domain-containing protein 3A (ATAD3A) stabilizes the folding of BiP to alleviate ER stress and promote cancer cell survival. Proliferator-activated receptor-gamma coactivator 1-α (PGC-1α) is highly expressed in 5-fluorouracil-resistant CRC cells and attenuates ER stress in 5-fluorouracil-resistant CRC cells, inhibiting cell apoptosis. Allyl isothiocyanate (AITC) induces ER stress by up-regulating ATF6, leading to cytosolic Ca2+ release, thereby modulating the apoptotic signaling pathway activated by the mitochondrial pathway. 2α,3α,24-Thrihydroxyurs-12-en-28-oicacid (TEOA) increases glucose-regulated protein 78 (GRP78) expression, promotes PERK and eukaryotic translation initiation factor-2α (eIF2α) phosphorylation, leading to up-regulation of C/EBP homologous protein (CHOP) expression. Oleander leaf phenol extract (PEOL) increases intracellular Ca2+ levels and CHOP expression in CRC cells, triggering ER stress-induced apoptosis. Jolkinolide B (JB), melatonin, ciclopirox (CPX), and 5, 3′-dihydroxy-3, 7, 4′-triethoxyflavone (TEF) influence Ca2+ homeostasis, leading to ER stress and cell death in CRC. The orange figure indicates overexpression. The blue figure indicates underexpression.

Credit

Lanshu Xiao, Yao Wei, Yiping Qin, Bianqin Guo

Usage Restrictions

Credit must be given to the creator. Only noncommercial uses of the work are permitted. No derivatives or adaptations of the work are permitted.

License

CC BY-NC-ND

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.