bims-unfpre 2022-06-19 papers

Issue of 2022–06–19
two papers selected by
Susan Logue, University of Manitoba

Cell Rep. 2022 Jun 14. pii: S2211-1247(22)00718-5. [Epub ahead of print]39(11): 110936

Enhanced metabolism and negative regulation of ER stress support higher erythropoietin production in HEK293 cells.

Rasool Saghaleyni, Magdalena Malm, Noah Moruzzi, Jan Zrimec, Ronia Razavi, Num Wistbacka, Hannes Thorell, Anton Pintar, Andreas Hober, Fredrik Edfors, Veronique Chotteau, Per-Olof Berggren, Luigi Grassi, Aleksej Zelezniak, Thomas Svensson, Diane Hatton, Jens Nielsen, Jonathan L Robinson, Johan Rockberg.

Recombinant protein production can cause severe stress on cellular metabolism, resulting in limited titer and product quality. To investigate cellular and metabolic characteristics associated with these limitations, we compare HEK293 clones producing either erythropoietin (EPO) (secretory) or GFP (non-secretory) protein at different rates. Transcriptomic and functional analyses indicate significantly higher metabolism and oxidative phosphorylation in EPO producers compared with parental and GFP cells. In addition, ribosomal genes exhibit specific expression patterns depending on the recombinant protein and the production rate. In a clone displaying a dramatically increased EPO secretion, we detect higher gene expression related to negative regulation of endoplasmic reticulum (ER) stress, including upregulation of ATF6B, which aids EPO production in a subset of clones by overexpression or small interfering RNA (siRNA) knockdown. Our results offer potential target pathways and genes for further development of the secretory power in mammalian cell factories.

Keywords: ATF6B; CP: Cell biology; CP: Molecular biology; Cell engineering; GFP; HEK293; erythropoietin; protein production; ribosome heterogeneity; secretory pathways

DOI: https://doi.org/10.1016/j.celrep.2022.110936

Am J Cancer Res. 2022 ;12(5): 2277-2292

The role and therapeutic implication of endoplasmic reticulum stress in inflammatory cancer transformation.

Yuan Li, Lu Lu, Guangtao Zhang, Guang Ji, Hanchen Xu.

Endoplasmic reticulum (ER) stress occurs when proteins are affected by various factors, fail to fold properly into higher structures and accumulate in the lumen of the ER, which activates the unfolded protein response (UPR) to restore normal cellular function or induce apoptosis as a self-protective mechanism. However, a growing number of studies have shown that the three branches of ER stress and the UPR can mediate inflammation and cancer development by interacting with inflammatory transformation-related signaling pathways. Targeting the UPR, especially the use of small molecules that target the active sites of the enzymes IRE1α and PERK and BIP/GRP78 inhibitors are potential strategies for treating tumors and have shown promising results in some tumor models. Therefore, in this review, we summarize the progress of ER stress/UPR research and the signaling pathways associated with inflammatory cancer transformation, provide an in-depth description of the mechanisms of these pathways, and outline strategies in the field of UPR biology in tumor therapy to provide new ideas for the mechanisms of inflammatory cancer transformation and tumor-related treatment.

Keywords: ER stress; inflammatory cancer transformation; targeted therapy; unfolded protein response