bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒07‒28
four papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. J Biol Chem. 2019 Jul 26. pii: jbc.RA119.008353. [Epub ahead of print]
    Xia Z, Wu S, Wei X, Liao Y, Yi P, Liu Y, Liu J, Liu J.
      Hypoxia occurs in many human solid tumors and activates multiple cellular adaptive response pathways, including the unfolded protein response (UPR) in the endoplasmic reticulum (ER). Wnt/β-catenin signaling plays a critical role in tumorigenesis, and β-catenin has been shown to enhance hypoxia-inducible factor 1α (HIF1α)-activated gene expression, thereby supporting cell survival during hypoxia. However, the molecular interplay between hypoxic ER stress, Wnt/β-catenin signaling, and HIF1α-mediated gene regulation during hypoxia remains incompletely understood. Here, we report that hypoxic ER stress reduces β-catenin stability, which, in turn, enhances the activity of spliced X-box-binding protein 1 (XBP1s), a transcription factor and signal transducer of the UPR, in HIF1α-mediated hypoxic responses. We observed that in the RKO colon cancer cell line, which possesses a Wnt-stimulated β-catenin signaling cascade, increased ER stress during hypoxia is accompanied by a reduction in LDL receptor-related protein 6 (LRP6), and this reduction in LRP6 decreased β-catenin accumulation and impaired Wnt/β-catenin signaling. Of note, β-catenin interacted with both XBP1s and HIF1α, suppressing XBP1s-mediated augmentation of HIF1α target genes expression. Furthermore, Wnt stimulation or β-catenin overexpression blunted XBP1s-mediated cell survival under hypoxia. Together, these results reveal an unanticipated role for the Wnt/β-catenin pathway in hindering hypoxic UPR-mediated responses that increase cell survival. Our findings suggest that the molecular cross-talks between hypoxic ER stress, LRP6/β-catenin signaling, and the HIF1α pathway may represent an unappreciated mechanism that enables some tumor subtypes to survival and grow in hypoxic conditions.
    Keywords:  Wnt signaling; X-box binding protein 1 (XBP1); cancer biology; endoplasmic reticulum stress (ER stress); hypoxia-inducible factor (HIF)
    DOI:  https://doi.org/10.1074/jbc.RA119.008353
  2. Eur J Pharmacol. 2019 Jul 17. pii: S0014-2999(19)30505-9. [Epub ahead of print] 172553
    Mohan S, R PRM, Brown L, Ayyappan P, G RK.
      Endoplasmic reticulum (ER) stress, a change in the ER homeostasis, leads to initiation of the unfolded protein response (UPR). The primary functions of the UPR are to restore the ER's physiological activity and coordinate the apoptotic and adaptive responses. Pathophysiological conditions that augment ER stress include hypoxia, misfolded and/or mutated protein accumulation, and high glucose. Prolonged ER stress is a critical factor in the pathogenesis of metabolic syndrome including type 2 diabetes mellitus, cardiovascular diseases, atherosclerosis, obesity, and fatty liver disease. UPR is a complex homeostatic pathway between newly synthesized proteins and their maturation, although the regulatory mechanisms contributing to the misfolded protein response and the possible therapeutic strategies are yet to be clarified. Therefore, a comprehensive understanding of the underlying molecular mechanisms is necessary to develop therapeutic interventions targeting ER stress response. In this review, we discuss the role of ER stress and misfolded protein response signaling in the pathogenesis of metabolic syndrome, highlighting the main functions of UPR components. We have emphasized the use of novel small molecular chemical chaperones, considered as modulators of ER stress. The initial studies with these chemical chaperones are promising, but detailed studies are required to define their efficacy and adverse effects during therapeutic use in humans.
    Keywords:  Cardiovascular diseases; Diabetes; ER stress; Liver; Obesity; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.ejphar.2019.172553
  3. Front Immunol. 2019 ;10 1530
    de Looff M, de Jong S, Kruyt FAE.
      Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) signaling is far more complex than initially anticipated and can lead to either anti- or protumorigenic effects, hampering the successful clinical use of therapeutic TRAIL receptor agonists. Cell autonomous resistance mechanisms have been identified in addition to paracrine factors that can modulate apoptosis sensitivity. The tumor microenvironment (TME), consisting of cellular and non-cellular components, is a source for multiple signals that are able to modulate TRAIL signaling in tumor and stromal cells. Particularly immune effector cells, also part of the TME, employ the TRAIL/TRAIL-R system whereby cell surface expressed TRAIL can activate apoptosis via TRAIL receptors on tumor cells, which is part of tumor immune surveillance. In this review we aim to dissect the impact of the TME on signaling induced by endogenous and exogenous/therapeutic TRAIL, thereby distinguishing different components of the TME such as immune effector cells, neutrophils, macrophages, and non-hematopoietic stromal cells. In addition, also non-cellular biochemical and biophysical properties of the TME are considered including mechanical stress, acidity, hypoxia, and glucose deprivation. Available literature thus far indicates that tumor-TME interactions are complex and often bidirectional leading to tumor-enhancing or tumor-reducing effects in a tumor model- and tumor type-dependent fashion. Multiple signals originating from different components of the TME simultaneously affect TRAIL receptor signaling. We conclude that in order to unleash the full clinical potential of TRAIL receptor agonists it will be necessary to increase our understanding of the contribution of different TME components on outcome of therapeutic TRAIL receptor activation in order to identify the most critical mechanism responsible for resistance, allowing the design of effective combination treatments.
    Keywords:  TME; TRAIL; cancer; cytokines; immune suppression
    DOI:  https://doi.org/10.3389/fimmu.2019.01530
  4. Mol Ther Nucleic Acids. 2019 Jun 06. pii: S2162-2531(19)30150-7. [Epub ahead of print]17 504-515
    Liu XQ, Duan LS, Chen YQ, Jin XJ, Zhu NN, Zhou X, Wei HW, Yin L, Guo JR.
      Impaired wound healing is a debilitating complication of diabetes. The long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been recognized to be differentially expressed in various diseases. However, its underlying mechanism in diabetes has not been fully understood. Notably, we aim to examine the expression of MALAT1 in diabetic mice and its role in wound healing involving the hypoxia-inducible factor-1α (HIF-1α) signaling pathway with a modified autologous blood preservative solution reported. A mouse model of diabetes was established. MALAT1 was identified to promote the activation of the HIF-1α signaling pathway and to be enriched in autologous blood through modified preservation, which might facilitate the improvement of physiological function of blood cells. Through gain- or loss-of-function approaches, viability of fibroblasts cultured in high glucose, wound healing of mice, and collagen expression in wound areas were enhanced by MALAT1 and HIF-1α. Taken together, the present study demonstrated that the physiological status of mouse blood was effectively improved by modified autologous blood preservation, which exhibited upregulated MALAT1, thereby accelerating the fibroblast activation and wound healing in diabetic mice via the activation of the HIF-1α signaling pathway. The upregulation of MALAT1 activating the HIF-1α signaling pathway provides a novel insight into drug targets against diabetes.
    Keywords:  HIF-1α signaling pathway; diabetic mice; long non-coding RNA MALAT1; modified autologous blood transfusion; wound healing
    DOI:  https://doi.org/10.1016/j.omtn.2019.05.020