bims-stacyt 2020-12-27 papers

Cell Metab. 2020 Dec 09. pii: S1550-4131(20)30604-5. [Epub ahead of print]

Intercellular Transmission of Hepatic ER Stress in Obesity Disrupts Systemic Metabolism.

Amir Tirosh, Gurol Tuncman, Ediz S Calay, Moran Rathaus, Idit Ron, Amit Tirosh, Abdullah Yalcin, Yankun G Lee, Rinat Livne, Sophie Ron, Neri Minsky, Ana Paula Arruda, Gökhan S Hotamisligil.

Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associated insulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increased connexin 43 (Cx43)-mediated intercellular communication has been implicated in tissue-adaptive and -maladaptive response to various chronic stresses. Here, we demonstrate that in hepatocytes, ERS results in increased Cx43 expression and cell-cell coupling. Co-culture of ER-stressed "donor" cells resulted in intercellular transmission of ERS and dysfunction to ERS-naive "recipient" cells ("bystander response"), which could be prevented by genetic or pharmacologic suppression of Cx43. Hepatocytes from obese mice were able to transmit ERS to hepatocytes from lean mice, and mice lacking liver Cx43 were protected from diet-induced ERS, insulin resistance, and hepatosteatosis. Taken together, our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling allows intercellular propagation of ERS. This novel maladaptive response to over-nutrition exacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-body glucose metabolism.

Keywords: connexin 43; diabetes; endoplasmic reticulum stress; gap junctions; insulin resistance; intercellular communication; unfolded protein response

DOI: https://doi.org/10.1016/j.cmet.2020.11.009

Cancer Lett. 2020 Dec 18. pii: S0304-3835(20)30681-9. [Epub ahead of print]

The oncogenic and clinical implications of lactate induced immunosuppression in the tumour microenvironment.

Conall Hayes, Claire Donohoe, Maria Davern, Noel E Donlon.

The tumour microenvironment is of critical importance in cancer development and progression and includes the surrounding stromal and immune cells, extracellular matrix, and the milieu of metabolites and signalling molecules in the intercellular space. To support sustained mitotic activity cancer cells must reconfigure their metabolic phenotype. Lactate is the major by-product of such metabolic alterations and consequently, accumulates in the tumour. Lactate actively contributes to immune evasion, a hallmark of cancer, by directly inhibiting immune cell cytotoxicity and proliferation. Furthermore, lactate can recruit and induce immunosuppressive cell types, such as regulatory T cells, tumour-associated macrophages, and myeloid-derived suppressor cells which further suppress anti-tumour immune responses. Given its roles in oncogenesis, measuring intratumoural and systemic lactate levels has shown promise as a both predictive and prognostic biomarker in several cancer types. The efficacies of many anti-cancer therapies are limited by an immunosuppressive TME in which lactate is a major contributor, therefore, targeting lactate metabolism is a priority. Developing inhibitors of key proteins in lactate metabolism such as GLUT1, hexokinase, LDH, MCT and HIF have shown promise in preclinical studies, however there is a corresponding lack of success in human trials so far. This may be explained by a weakness of preclinical models that fail to reproduce the complexities of metabolic interactions in natura. The future of these therapies may be as an adjunct to more conventional treatments.

Keywords: Immune evasion; Metabolic reprogramming; Oncometabolite; Predictive and prognostic biomarker; Warburg effect

DOI: https://doi.org/10.1016/j.canlet.2020.12.021

Eur J Pharmacol. 2020 Dec 17. pii: S0014-2999(20)30922-5. [Epub ahead of print] 173817

IL-6 promotes nuclear translocation of HIF-1α to aggravate chemoresistance of ovarian cancer cells.

Shiwen Xu, Chunyan Yu, Xiaoxia Ma, Yan Li, Yangyang Shen, Yan Chen, Suhui Huang, Tongshuo Zhang, Weimin Deng, Yue Wang.

The inflammatory milieu in tumor modulates the resistance to the conventional antitumoral therapies. Interleukin-6 (IL-6), a pleiotropic pro-inflammatory cytokine and a crucial mediator of tumor development, has been targeted as a therapeutic strategy to overcome chemoresistance in the treatment of tumors. The protein levels and nuclear translocation of HIFs (hypoxia-inducible factors), such as HIF-1α, are linked to the drug resistance of tumor cells. However, whether IL-6 promotes the nuclear translocation of HIF-1α and the related mechanism remain to be investigated. We applied two ovarian cancer (OvCa) cell lines, A2780 cells and SKOV3 cells for the in vivo and in vitro studies. We found that IL-6 up-regulates the HIF-1α expression via the signal transducer and activator of transcription 3 (STAT3) signaling under hypoxia in either endogenous or exogenous way, and then we proved that IL-6 enhances the transcriptional activity of HIF-1α via the STAT3 signaling. Further mechanism research revealed that IL-6 promotes the nuclear translocation of HIF-1α through the STAT3 signaling under hypoxia. Proliferation assay and apoptosis assay were applied and proved that IL-6 enhances the chemoresistance of OvCa cells against cisplatin through the upregulation of HIF-1α via the STAT3 signaling in vitro. The In vivo studies confirmed the effect of IL-6 in increasing the chemoresistance of OvCa cells against cisplatin through the IL-6/STAT3/HIF-1α loop in the animal models. Our data elucidates the explicit mechanism of IL-6/STAT3/HIF-1α loop in OvCa and also provides new insights into the development of different approaches for the inflammation-induced and hypoxia-induced resistance in tumor therapies.

Keywords: Chemoresistance; IL-6/STAT3/HIF-1α; Nuclear translocation; Ovarian cancer

DOI: https://doi.org/10.1016/j.ejphar.2020.173817

Cancers (Basel). 2020 Dec 17. pii: E3802. [Epub ahead of print]12(12):

Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations.

Ryan C Augustin, Greg M Delgoffe, Yana G Najjar.

Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely on a robust infiltration of T-cells into the tumor microenvironment (TME) for an effective response. While early efforts relied on quantifying tumor infiltrating lymphocytes (TIL) in the TME, characterizing the functional quality and degree of TIL exhaustion correlates more strongly with ICI response. Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance. This review will explore these biochemical pathways linked to immune cell dysfunction in the TME and highlight potential adjunctive therapies to be used alongside current IMT.

Keywords: cellular energetics; immunometabolism; immunotherapy

DOI: https://doi.org/10.3390/cancers12123802

Trends Pharmacol Sci. 2020 Dec 16. pii: S0165-6147(20)30265-0. [Epub ahead of print]

Targeting the Immune System for Ischemic Stroke.

Shenpeng R Zhang, Thanh G Phan, Christopher G Sobey.

Stroke is responsible for almost 6 million deaths and more than 10% of all mortalities each year, and two-thirds of stroke survivors remain disabled. With treatments for ischemic stroke still limited to clot lysis and/or mechanical removal, new therapeutic targets are desperately needed. In this review, we provide an overview of the complex mechanisms of innate and adaptive immune cell-mediated inflammatory injury, that exacerbates infarct development for several days after stroke. We also highlight the features of poststroke systemic immunodepression that commonly leads to infections and some mortalities, and argue that safe and effective therapies will need to balance pro- and anti-inflammatory mechanisms in a time-sensitive manner, to maximize the likelihood of an improved long-term outcome.

Keywords: immune cells; immunotherapy; infection; inflammation; penumbra; stroke

DOI: https://doi.org/10.1016/j.tips.2020.11.010