bims-ershed 2022-10-16 papers

Issue of 2022‒10‒16
three papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

Exp Cell Res. 2022 Oct 06. pii: S0014-4827(22)00369-X. [Epub ahead of print]421(1): 113376

IRE1α-XBP1 regulates PDK1-dependent induction of epithelial-mesenchymal transition in non-small cell lung cancer cells.

Xike Mao, Chenxi Yu, Feng Yin, Wenjiao Xu, Yonghan Pan, Bowen Yang, Tao Huang, Siling Chen, Wenge Luo, Tianyu Su, Zhihao Wu.

Mounting evidence indicates that activation of unfolded protein response (UPR) and metabolic reprogramming contribute to cancer cell migration and invasion, but the molecular mechanism of pro-EMT program through a coordinated action of UPR with metabolism has not been defined. In this study, we utilized ER stress-inducing reagent, thapsigargin (TG), to induced pharmacologic ER stress in lung cancer cells. Here. We report that the branch of UPR, IRE1α-XBP1 pathway plays a pivotal role in reprogramming lung cancer cell metabolism. At the molecular level, the expression of pyruvate dehydrogenase kinase-1 (PDK-1) is directly induced by XBP1 as a consequence of UPR activation, thus facilitating aerobic glycolysis and lactate production. We also demonstrated that PDK1 serves as a downstream element of UPR activation in induction of Snail and EMT program. In addition, PDK1-induced Snail was dependent on the lactate production derived from metabolic reprogramming. Our findings reveal a critical role of lactate in pro-invasion events and establishes a direct connection between ER-stress and metabolic reprogramming in facilitating cancer cell progression.

Keywords: IRE1α-XBP1 pathway; Metabolic reprogramming; Pyruvate dehydrogenase kinase-1 (PDK-1); Snail; Unfolded protein response (UPR)

DOI: https://doi.org/10.1016/j.yexcr.2022.113376

Biochem Biophys Res Commun. 2022 Sep 29. pii: S0006-291X(22)01360-2. [Epub ahead of print]632 158-164

KIRA8 attenuates non-alcoholic steatohepatitis through inhibition of the IRE1α/XBP1 signalling pathway.

Shiting Zhao, Xiaomin Liu, Lei Li, Xinyu Kong, Wei Sun, Kerry Loomes, Tao Nie, Xiaoyan Hui, Donghai Wu.

Endoplasmic reticulum (ER) stress is enhanced in non-alcoholic steatohepatitis (NASH). Among three signalling pathways, the IRE1α/XBP1 signalling pathway is strongly implicated in the pathogenesis of NASH but its significance is still largely uncharacterised. In this report, we constructed a hepatocyte-specific XBP1-Luciferase knock-in mouse model that allows in vivo monitoring of the IRE1α/XBP1 activity in hepatocytes. Using this mouse model, we found that IRE1α/XBP1 was activated within hepatocytes during the pathogenesis of NASH. Significantly, a specific IRE1α kinase-inhibiting RNase attenuator, KIRA8, attenuated NASH in mice. In conclusion, our hepatocyte-specific XBP1 splicing reporter mouse represents a valid model for research and drug development of NASH, which showed that the IRE1α-induced XBP splicing is potentiated in hepatocytes during pathogenesis of NASH. Furthermore, we carried out the proof-of-concept study to demonstrate that the allosteric IRE1α RNase inhibitor serves as a promising therapeutic agent for the treatment of NASH.

Keywords: IRE1α; KIRA8; NASH; Reporter mouse model; XBP1 splicing

DOI: https://doi.org/10.1016/j.bbrc.2022.09.098

Cancers (Basel). 2022 Oct 05. pii: 4870. [Epub ahead of print]14(19):

The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment.

Sylwia Bartoszewska, James F Collawn, Rafal Bartoszewski.

Despite our understanding of the unfolded protein response (UPR) pathways, the crosstalk between the UPR and the complex signaling networks that different cancers utilize for cell survival remains to be, in most cases, a difficult research barrier. A major problem is the constant variability of different cancer types and the different stages of cancer as well as the complexity of the tumor microenvironments (TME). This complexity often leads to apparently contradictory results. Furthermore, the majority of the studies that have been conducted have utilized two-dimensional in vitro cultures of cancer cells that were exposed to continuous hypoxia, and this approach may not mimic the dynamic and cyclic conditions that are found in solid tumors. Here, we discuss the role of intermittent hypoxia, one of inducers of the UPR in the cellular component of TME, and the way in which intermittent hypoxia induces high levels of reactive oxygen species, the activation of the UPR, and the way in which cancer cells modulate the UPR to aid in their survival. Although the past decade has resulted in defining the complex, novel non-coding RNA-based regulatory networks that modulate the means by which hypoxia influences the UPR, we are now just to beginning to understand some of the connections between hypoxia, the UPR, and the TME.

Keywords: ER-stress; TME; UPRmt; cell fate determination; hypoxia-reoxygenation injury

DOI: https://doi.org/10.3390/cancers14194870