bims-stacyt 2023-07-23 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023–07–23
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

GDF15 increases insulin action in the liver and adipose tissue via a β-adrenergic receptor-mediated mechanism.
Endoplasmic reticulum stress: a novel targeted approach to repair bone defects by regulating osteogenesis and angiogenesis.
Intermittent hypoxia inhibits anti-tumor immune response via regulating PD-L1 expression in lung cancer cells and tumor-associated macrophages.
Sorafenib promotes hepatocellular carcinoma invasion via interleukin-6/HIF-1α/PFKFB3.
Differential effects of sugar and fat on adipose tissue inflammation.
Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment.
2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer's resilience.

Cell Metab. 2023 Jul 12. pii: S1550-4131(23)00226-7. [Epub ahead of print]

GDF15 increases insulin action in the liver and adipose tissue via a β-adrenergic receptor-mediated mechanism.

Kim A Sjøberg, Casper M Sigvardsen, Abdiel Alvarado-Diaz, Nicoline Resen Andersen, Mark Larance, Randy J Seeley, Peter Schjerling, Jakob G Knudsen, Georgios Katzilieris-Petras, Christoffer Clemmensen, Sebastian Beck Jørgensen, Katrien De Bock, Erik A Richter.

  Growth differentiation factor 15 (GDF15) induces weight loss and increases insulin action in obese rodents. Whether and how GDF15 improves insulin action without weight loss is unknown. Obese rats were treated with GDF15 and displayed increased insulin tolerance 5 h later. Lean and obese female and male mice were treated with GDF15 on days 1, 3, and 5 without weight loss and displayed increased insulin sensitivity during a euglycemic hyperinsulinemic clamp on day 6 due to enhanced suppression of endogenous glucose production and increased glucose uptake in WAT and BAT. GDF15 also reduced glucagon levels during clamp independently of the GFRAL receptor. The insulin-sensitizing effect of GDF15 was completely abrogated in GFRAL KO mice and also by treatment with the β-adrenergic antagonist propranolol and in β1,β2-adrenergic receptor KO mice. GDF15 activation of the GFRAL receptor increases β-adrenergic signaling, in turn, improving insulin action in the liver and white and brown adipose tissue.

Keywords:  GFRAL receptor; adrenergic receptors; appetite control; euglycemic clamp; glucagon; glucose metabolism; insulin resistance; insulin sensitivity

DOI:  https://doi.org/10.1016/j.cmet.2023.06.016
J Transl Med. 2023 Jul 18. 21(1): 480

Endoplasmic reticulum stress: a novel targeted approach to repair bone defects by regulating osteogenesis and angiogenesis.

Tingyu Wu, Yaping Jiang, Weipeng Shi, Yingzhen Wang, Tao Li.

  Bone regeneration therapy is clinically important, and targeted regulation of endoplasmic reticulum (ER) stress is important in regenerative medicine. The processing of proteins in the ER controls cell fate. The accumulation of misfolded and unfolded proteins occurs in pathological states, triggering ER stress. ER stress restores homeostasis through three main mechanisms, including protein kinase-R-like ER kinase (PERK), inositol-requiring enzyme 1ɑ (IRE1ɑ) and activating transcription factor 6 (ATF6), collectively known as the unfolded protein response (UPR). However, the UPR has both adaptive and apoptotic effects. Modulation of ER stress has therapeutic potential for numerous diseases. Repair of bone defects involves both angiogenesis and bone regeneration. Here, we review the effects of ER stress on osteogenesis and angiogenesis, with emphasis on ER stress under high glucose (HG) and inflammatory conditions, and the use of ER stress inducers or inhibitors to regulate osteogenesis and angiogenesis. In addition, we highlight the ability for exosomes to regulate ER stress. Recent advances in the regulation of ER stress mediated osteogenesis and angiogenesis suggest novel therapeutic options for bone defects.

Keywords:  Angiogenesis; Bone defects; Endoplasmic reticulum stress; Exosome; High glucose; Inflammation; Osteogenesis; Unfolded protein response

DOI:  https://doi.org/10.1186/s12967-023-04328-8
Int Immunopharmacol. 2023 Jul 19. pii: S1567-5769(23)00977-3. [Epub ahead of print]122 110652

Intermittent hypoxia inhibits anti-tumor immune response via regulating PD-L1 expression in lung cancer cells and tumor-associated macrophages.

Zhilei Cui, Zhengshang Ruan, Meigui Li, Rongrong Ren, Yizong Ma, Junxiang Zeng, Jinyuan Sun, Wenjing Ye, Weiguo Xu, Xuejun Guo, Dengfei Xu, Linlin Zhang.

  Accumulating evidence has shown an increased tumor incidence and reduced survival rate in cancer patients with obstructive sleep apnea (OSA). Although intermittent hypoxia is known to play a crucial role, the molecular mechanism by which intermittent hypoxia accelerates lung cancer progression remains to be elucidated.A lung cancer xenograft mouse model was established by subcutaneously injecting LLC cells into C57BL/6 mice. The tumor-bearing mice were exposed to either normoxia or intermittent hypoxia and received either IgG2a, anti-programmed death ligand-1 (PD-L1), PX-478, or anti-PD-L1 + PX-478 treatment.A significant upregulation of tumor associated macrophages (TAMs) papulation and PD-L1 levels was observed in lung adenocarcinoma patients with OSA. We further confirmed that hypoxia-inducible factor-1 alpha (HIF-1α) regulates PD-L1 at transcriptional levels, mainly through binding to the hypoxia response element 4. Using a lung cancer xenograft mouse model, we observed that intermittent hypoxia exposed tumors grew faster and bigger with upregulated HIF-1α and PD-L1 expression, enhanced TAMs and Treg populations, and reduced cytotoxic T cells and cytokine secretion. Finally, we found a combination of PX-478 and anti-PD-L1 exerted an encouraging tumor inhibition effect compared to single treatment. Combination therapies based on HIF-1α and PD-L1 blockade might serve as a promising strategy to treat lung cancer patients with OSA.

Keywords:  Hypoxia; Lung cancer; OSA; PD-L1

DOI:  https://doi.org/10.1016/j.intimp.2023.110652
J Cancer. 2023 ;14(10): 1859-1874

Sorafenib promotes hepatocellular carcinoma invasion via interleukin-6/HIF-1α/PFKFB3.

Pengyuan Zhuang, Dong Wang, Kewei Zhang, Jiandong Wang, Jun Shen.

  Background: Although sorafenib is adopted as the first-line treatment for unresectable liver cancer, the antitumor efficacy is severely limited by the pro-invasive side effect. Methods: To explore the underlying mechanisms, various-dosage sorafenib was applied to survey its effect on cell invasion in HCCLM3 and PLC cell models. Results: Our results revealed that high-dosage sorafenib inhibited liver cancer cell invasion. By contrast, sorafenib with low and median dosages promoted the invasion. In vivo studies showed that sorafenib with a median dosage increased the intrahepatic metastasis (IHM) and lung metastasis (LM) of liver cancer cells, while sorafenib with a high dosage inhibited IHM and LM. Then, bioinformatics analysis indicated that HIF-1α, IL-6, and PFKFB3 were associated with the sorafenib resistance. In vitro models showed that the pro-invasive effect was mediated by IL-6/HIF-1α/PFKFB3 regulation in dosage- and time-dependent manners. PFKFB3 knockdown confirmed that PFKFB3 promoted HCCLM3 cell migration via modulating EMT-related markers. Furthermore, we found that sorafenib upregulated PFKFB3 by IL-6/HIF-1α in a time-dependent manner, without direct effect on PFKFB3 expression. Conclusions: In summary, these results demonstrated that sorafenib could dose-dependently promote cell invasion, intrahepatic and lung metastasis in hepatocellular carcinoma through IL-6/HIF-1α mediated PFKFB3 activation, providing novel insights to improve the therapeutic efficacy of sorafenib.

Keywords:  IL-6; PFKFB3; hepatocellular carcinoma; invasion; sorafenib

DOI:  https://doi.org/10.7150/jca.84451
iScience. 2023 Jul 21. 26(7): 107163

Differential effects of sugar and fat on adipose tissue inflammation.

Tracey Avequin, Kin H Lau, Althea N Waldhart, Hannah Guak, Holly Dykstra, Connie Krawczyk, Ning Wu.

  Obese individuals experience low grade inflammation initiated within their adipose tissue. However, the early events that lead to the release of these inflammatory factors from adipose tissue are poorly characterized. To separate glucose effects from lipid effects on adipose tissue, we used an adipose-specific TXNIP knockout model where excess basal glucose influx into adipocytes led to modest increase in adiposity without using high fat diet. We found an uncoupling of two events that are generally presumed to be coregulated: (1) an increase of adipose tissue macrophage (ATM) number; and (2) pro-inflammatory activation of ATMs. These two events are associated with different triggering signals: elevated free fatty acids output and extracellular matrix remodeling with increased ATM number, whereas decreased adiponectin level with activated ATM. This separation reflects non-overlapping pathways regulated by glucose and lipids in adipocytes, and neither group alone is sufficient to elicit the full inflammatory response in adipose tissue.

Keywords:  Cell biology; Endocrinology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2023.107163
Nat Commun. 2023 Jul 20. 14(1): 4253

Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment.

Markus Haake, Beatrice Haack, Tina Schäfer, Patrick N Harter, Greta Mattavelli, Patrick Eiring, Neha Vashist, Florian Wedekink, Sabrina Genssler, Birgitt Fischer, Julia Dahlhoff, Fatemeh Mokhtari, Anastasia Kuzkina, Marij J P Welters, Tamara M Benz, Lena Sorger, Vincent Thiemann, Giovanni Almanzar, Martina Selle, Klara Thein, Jacob Späth, Maria Cecilia Gonzalez, Carmen Reitinger, Andrea Ipsen-Escobedo, Kilian Wistuba-Hamprecht, Kristin Eichler, Katharina Filipski, Pia S Zeiner, Rudi Beschorner, Renske Goedemans, Falk Hagen Gogolla, Hubert Hackl, Rogier W Rooswinkel, Alexander Thiem, Paula Romer Roche, Hemant Joshi, Dirk Pühringer, Achim Wöckel, Joachim E Diessner, Manfred Rüdiger, Eugen Leo, Phil F Cheng, Mitchell P Levesque, Matthias Goebeler, Markus Sauer, Falk Nimmerjahn, Christine Schuberth-Wagner, Stefanie von Felten, Michel Mittelbronn, Matthias Mehling, Andreas Beilhack, Sjoerd H van der Burg, Angela Riedel, Benjamin Weide, Reinhard Dummer, Jörg Wischhusen.

Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.

DOI: https://doi.org/10.1038/s41467-023-39817-3
Neuron. 2023 Jul 11. pii: S0896-6273(23)00472-5. [Epub ahead of print]

2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer's resilience.

Amit Kumar, Saravanan S Karuppagounder, Yingxin Chen, Carlo Corona, Riki Kawaguchi, Yuyan Cheng, Mustafa Balkaya, Botir T Sagdullaev, Zhexing Wen, Charles Stuart, Sunghee Cho, Guo-Li Ming, Jürgen Tuvikene, Tõnis Timmusk, Daniel H Geschwind, Rajiv R Ratan.

  Intermittent fasting (IF) is a diet with salutary effects on cognitive aging, Alzheimer's disease (AD), and stroke. IF restricts a number of nutrient components, including glucose. 2-deoxyglucose (2-DG), a glucose analog, can be used to mimic glucose restriction. 2-DG induced transcription of the pro-plasticity factor, Bdnf, in the brain without ketosis. Accordingly, 2-DG enhanced memory in an AD model (5xFAD) and functional recovery in an ischemic stroke model. 2-DG increased Bdnf transcription via reduced N-linked glycosylation, consequent ER stress, and activity of ATF4 at an enhancer of the Bdnf gene, as well as other regulatory regions of plasticity/regeneration (e.g., Creb5, Cdc42bpa, Ppp3cc, and Atf3) genes. These findings demonstrate an unrecognized role for N-linked glycosylation as an adaptive sensor to reduced glucose availability. They further demonstrate that ER stress induced by 2-DG can, in the absence of ketosis, lead to the transcription of genes involved in plasticity and cognitive resilience as well as proteostasis.

Keywords:  2-deoxyglucose; Alzheimer’s disease; N-linked glycosylation; activating transcription factor 4; brain-derived neurotrophic factor; cognitive function; endoplasmic reticulum stress; intermittent fasting; ischemic stroke; learning and memory

DOI:  https://doi.org/10.1016/j.neuron.2023.06.013