bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒11‒03
three papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. J Biol Chem. 2019 10 30. pii: jbc.REV119.007036. [Epub ahead of print]
    Huang S, Xing Y, Liu Y.
      Inositol-requiring enzyme 1 (IRE1) is an endoplasmic reticulum (ER)-resident transmembrane protein that senses ER stress and is evolutionarily conserved from yeast to humans. IRE1 possesses both Ser/Thr protein kinase and endoribonuclease (RNase) activities within its cytoplasmic domain and is activated through autophosphorylation and dimerization/oligomerization. It mediates a critical arm of the unfolded protein response (UPR) to manage ER stress provoked by lumenal overload of unfolded/misfolded proteins. Emerging lines of evidence have revealed that in mammals, IRE1α functions as a multifunctional signal transducer that responds to metabolic cues and nutrient stress conditions, exerting profound and broad effects on metabolic homeostasis. In this review, we cover recent advances in our understanding of how IRE1α integrates a variety of metabolic and stress signals and highlight its tissue-specific or context-dependent metabolic activities. We also discuss how dysregulation of this metabolic stress sensor during handling of excessive nutrients in cells contributes to the progression of obesity and metabolic disorders.
    Keywords:  ER-associated degradation; Endoplasmic reticulum to nucleus signaling 1 (Ern1); IRE1α; Metabolic inflammation; Nutrient sensing; Regulated IRE1-depedendent decay (RIDD); X-box binding protein 1 (XBP1); endoplasmic reticulum stress (ER stress); signal transduction; unfolded protein response (UPR)
  2. Matrix Biol. 2019 Oct 24. pii: S0945-053X(19)30372-5. [Epub ahead of print]
    Valle-Tenney R, Rebolledo D, Lipson KE, Brandan E.
      Several skeletal muscle diseases are characterized by fibrosis, the excessive accumulation of extracellular matrix. Transforming growth factor-β (TGF-β) and connective tissue growth factor (CCN2/CTGF) are two profibrotic factors augmented in fibrotic skeletal muscle, together with signs of reduced vasculature that implies a decrease in oxygen supply. We observed that fibrotic muscles are characterized by the presence of positive nuclei for hypoxia-inducible factor-1α (HIF-1α), a key mediator of the hypoxia response. However, it is not clear how a hypoxic environment could contribute to the fibrotic phenotype in skeletal muscle. We evaluated the role of hypoxia and TGF-β on CCN2 expression in vitro. Fibroblasts, myoblasts and differentiated myotubes were incubated with TGF-β1 under hypoxic conditions. Hypoxia and TGF-β1 induced CCN2 expression synergistically in myotubes but not in fibroblasts or undifferentiated muscle progenitors. This induction requires HIF-1α and the Smad-independent TGF-β signaling pathway. We performed in vivo experiments using pharmacological stabilization of HIF-1α or hypoxia-induced via hindlimb ischemia together with intramuscular injections of TGF-β1, and we found increased CCN2 expression. These observations suggest that hypoxic signaling together with TGF-β signaling, which are both characteristics of a fibrotic skeletal muscle environment, induce the expression of CCN2 in skeletal muscle fibers and myotubes.
    Keywords:  CCN2/CTGF; Fibrosis; HIF-1α; Hypoxia; Skeletal Muscle; TGF-β
  3. Cancer Res. 2019 Oct 31. pii: canres.1116.2019. [Epub ahead of print]
    Moore PC, Qi JY, Thamsen M, Ghosh R, Peng J, Gliedt MJ, Meza-Acevedo R, Warren RE, Hiniker A, Kim GE, Maly DJ, Backes BJ, Papa FR, Oakes SA.
      Master regulators of the unfolded protein response (UPR) IRE1alpha and PERK promote adaptation or apoptosis depending on the level of endoplasmic reticulum (ER) stress. While the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNETs) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. Genetic and pharmacologic modulation of IRE1alpha and PERK in cultured cells, xenograft and spontaneous genetic (RIP-Tag2) mouse models of PanNETs revealed that UPR signaling was optimized for adaptation and that inhibiting either IRE1alpha or PERK led to hyperactivation and apoptotic signaling through the reciprocal arm, thereby halting tumor growth and survival. These results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers with elevated ER stress.