bims-stacyt 2022-05-22 papers

Dev Cell. 2022 May 11. pii: S1534-5807(22)00286-6. [Epub ahead of print]

Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis.

Roxana E Oberkersch, Giovanna Pontarin, Matteo Astone, Marianna Spizzotin, Liaisan Arslanbaeva, Giovanni Tosi, Emiliano Panieri, Sara Ricciardi, Maria Francesca Allega, Alessia Brossa, Paolo Grumati, Benedetta Bussolati, Stefano Biffo, Saverio Tardito, Massimo M Santoro.

Angiogenesis, the active formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings. Recent evidence supports cell metabolism as a critical regulator of angiogenesis. However, whether and how cell metabolism regulates endothelial growth factor receptor levels and nucleotide synthesis remains elusive. We here shown in both human cell lines and mouse models that during developmental and pathological angiogenesis, endothelial cells (ECs) use glutaminolysis-derived glutamate to produce aspartate (Asp) via aspartate aminotransferase (AST/GOT). Asp leads to mTORC1 activation which, in turn, regulates endothelial translation machinery for VEGFR2 and FGFR1 synthesis. Asp-dependent mTORC1 pathway activation also regulates de novo pyrimidine synthesis in angiogenic ECs. These findings identify glutaminolysis-derived Asp as a regulator of mTORC1-dependent endothelial translation and pyrimidine synthesis. Our studies may help overcome anti-VEGF therapy resistance by targeting endothelial growth factor receptor translation.

Keywords: angiogenesis; aspartate metabolism; endothelial metabolism; mTOR signalling; tumor angiogenesis

DOI: https://doi.org/10.1016/j.devcel.2022.04.018

Eur J Pharmacol. 2022 May 11. pii: S0014-2999(22)00273-4. [Epub ahead of print] 175012

Endoplasmic reticulum stress induces degradation of glucose transporter proteins during hyperglycemic hepatotoxicity: Role of PERK-eIF2α-ATF4 axis.

Vivek Kumar Pandey, Alpana Mathur, Mohammad Fareed Khan, Poonam Kakkar.

Hyperglycemia induced reactive oxygen species oxidize macromolecules including cellular proteins leading to their accumulation in Endoplasmic Reticulum (ER) lumen which in turn activates unfolded protein response (UPR) sensors including, PERK (Protein Kinase RNA-Like ER Kinase). Activated PERK induces ER associated degradation of misfolded proteins to lower the ER stress. In the present study, we hypothesized that ER stress leads to the degradation of glucose transporter proteins resulting in complex glucose metabolism. In vivo studies were carried out in the experimental model of hyperglycemia using streptozotocin/nicotinamide induced diabetic male Wistar rats. High glucose (30mM) treated HepG2 cells were used to perform the mechanistic study at different time points. PERK gene knockdown (siRNA transfection) and inhibition by ISRIB (Integrated Stress Response Inhibitor, a potent inhibitor of PERK signaling) confirmed the involvement of PERK axis in regulating the expression and translocation of hepatic glucose transporters. Co-immunoprecipitation and dual immunostaining studies further demonstrated increased degradation of GLUT proteins under high glucose conditions. Moreover, Morin (3,5,7,2',4' pentahydroxyflavone) treatment prevented PERK-eIF2α-ATF4 mediated degradation of glucose transporters and enhanced glucose uptake in both, HepG2 cells and diabetic rats. Targeting aberrant regulation of the expression and translocation of facilitative glucose transporter proteins (GLUT proteins) may provide novel therapeutic strategies for the better management of diabetes.

Keywords: ER-Stress; Flavonoid; Glucose transporters; Morin; Oxidative stress

DOI: https://doi.org/10.1016/j.ejphar.2022.175012

Bioessays. 2022 May 19. e2200026

The integrated stress response in the induction of mutant KRAS lung carcinogenesis: Mechanistic insights and therapeutic implications.

Antonis E Koromilas.

The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogramming of gene expression in stressed cells. While ISR promotes tumor survival under stress, its hyperactivation above a level of tolerance can also cause tumor death. The tumorigenic function of ISR has been recently demonstrated for lung adenocarcinomas (LUAD) with KRAS mutations. ISR mediates the translational repression of the dual-specificity phosphatase DUSP6 to stimulate ERK activity and LUAD growth. The significance of this finding is highlighted by the strong anti-tumor responses of ISR inhibitors in pre-clinical LUAD models. Elucidation of the mechanisms of ISR action in LUAD progression via cell-autonomous and immune regulatory mechanisms will provide a better understanding of its tumorigenic role to fully exploit its therapeutic potential in the treatment of a deadly form of cancer.

Keywords: KRAS oncogene; cancer therapeutics; lung adenocarcinoma; mRNA translation; oncogenic stress; transgenic mouse; translation initiation factor eIF2

DOI: https://doi.org/10.1002/bies.202200026

J Biol Chem. 2022 May 13. pii: S0021-9258(22)00470-7. [Epub ahead of print] 102030

Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1.

Gwen R Buel, Huy Dang, John M Asara, John Blenis, Anders P Mutvei.

The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase complex that promotes anabolic processes including protein, lipid, and nucleotide synthesis, while suppressing catabolic processes such as macroautophagy. mTORC1 activity is regulated by growth factors and amino acids which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Akt-dependent pathway, whereas the availabilities of amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. While it is relatively well described how acute changes in leucine and arginine levels affect mTORC1 signaling, the effects of prolonged amino acid deprivation remain less well understood. Here, we demonstrate that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, which reaches activation levels similar to those observed in nutrient-rich conditions. Surprisingly, we find that this reactivation is independent of the regeneration of amino acids by canonical autophagy or proteasomal degradation, but is dependent on PI3K/Akt signaling. Together, our data identify a novel crosstalk between the amino acid and PI3K/Akt signaling pathways upstream of mTORC1. These observations extend our understanding of the role of mTORC1 in growth-related diseases and indicate that dietary intervention by removal of leucine and/or arginine may be an ineffective therapeutic approach.

DOI: https://doi.org/10.1016/j.jbc.2022.102030

Cell Death Dis. 2022 May 20. 13(5): 478

Cancer associated fibroblast-derived CCL5 promotes hepatocellular carcinoma metastasis through activating HIF1α/ZEB1 axis.

Haixu Xu, Jie Zhao, Jinping Li, Zhifeng Zhu, Zhaohai Cui, Ran Liu, Rong Lu, Zhi Yao, Qiong Xu.

Cancer-associated fibroblasts (CAFs) are one of the most enriched components of Hepatocellular carcinoma (HCC) microenvironment, which are tightly related to the metastasis and invasion of HCC. We identified a mechanism by which CAF-derived chemokine CCL5 enhanced HCC metastasis by triggering the HIF1α/ZEB1 axis. We demonstrated that CAFs derived from HCC tissues promoted the migration and invasion of HCC cells and facilitated metastasis to the lung of NOD/SCID mice. Then the chemokine antibody array elucidated the higher chemokine CCL5 level secreted by CAFs than by paracancerous tissue fibroblasts (PTFs). Mechanistically, we found that CAF-derived CCL5 inhibited the ubiquitination and degradation of hypoxia-inducible factor 1 alpha (HIF1α) by binding to specific receptors, maintained HIF1α under normoxia, thereby up-regulated the downstream gene zinc finger enhancer-binding protein 1 (ZEB1) and induced epithelial-mesenchymal transition (EMT), ultimately validating its ability to promote lung metastasis of HCC. And this novel mechanism may have association with poor prognosis. Taken together, targeting CAF-derived CCL5 mediated HIF1α/ZEB1 cascade possibly propose a new therapeutic route for HCC.

DOI: https://doi.org/10.1038/s41419-022-04935-1