bims-stacyt 2024-12-29 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–12–29
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia.
Overexpression of Growth Differentiation Factor 15 Reduces Neuronal Cell Damage Induced by Oxygen-Glucose Deprivation/Reoxygenation via Inhibiting Endoplasmic Reticulum Stress-Mediated Ferroptosis.
Poststroke hyperglycemia dysregulates cap-dependent translation in neural cells.
Hypoxia-induced translation of collagen-modifying enzymes PLOD2 and P4HA1 is dependent on RBM4 and eIF4E2 in human colon cancer HCT116 cells.
Hypoglycaemic stimulation of macrophage cytokine release is suppressed by AMP-activated protein kinase activation.
The Role of Leukemia Inhibitory Factor in Cardiovascular Disease: Signaling in Inflammation, Coagulation, and Angiogenesis.
GLP-1 and IL-6 regulates obesity in the gut and brain.
Lactylation-driven TNFR2 expression in regulatory T cells promotes the progression of malignant pleural effusion.
NGF-mediated crosstalk: unraveling the influence of metabolic deregulation on the interplay between neural and pancreatic cancer cells and its impact on patient outcomes.
The evolving tumor-associated adipose tissue microenvironment in breast cancer: from cancer initiation to metastatic outgrowth.

Cell Death Discov. 2024 Dec 21. 10(1): 510

Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia.

Erica Pranzini, Livio Muccillo, Ilaria Nesi, Alice Santi, Caterina Mancini, Giulia Lori, Massimo Genovese, Tiziano Lottini, Giuseppina Comito, Anna Caselli, Annarosa Arcangeli, Lina Sabatino, Vittorio Colantuoni, Maria Letizia Taddei, Paolo Cirri, Paolo Paoli.

Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of body weight occurring in about 80% of cancer patients, frequently representing the leading cause of death. Dietary intervention is emerging as a promising therapeutic strategy to counteract cancer-induced wasting. Serine is the second most-consumed amino acid (AA) by cancer cells and has emerged to be strictly necessary to preserve skeletal muscle structure and functionality. Here, we demonstrate that decreased serine availability during tumor progression promotes myotubes diameter reduction in vitro and induces muscle wasting in in vivo mice models. By investigating the metabolic crosstalk between colorectal cancer cells and muscle cells, we found that incubating myotubes with conditioned media from tumor cells relying on exogenous serine consumption triggers pronounced myotubes diameter reduction. Accordingly, culturing myotubes in a serine-free medium induces fibers width reduction and suppresses the activation of the AKT-mTORC1 pathway with consequent impairment in protein synthesis, increased protein degradation, and enhanced expression of the muscle atrophy-related genes Atrogin1 and MuRF1. In addition, serine-starved conditions affect myoblast differentiation and mitochondrial oxidative metabolism, finally inducing oxidative stress in myotubes. Consistently, serine dietary deprivation strongly strengthens cancer-associated weight loss and muscle atrophy in mice models. These findings uncover serine consumption by tumor cells as a previously undisclosed driver in cancer cachexia, opening new routes for possible therapeutic approaches.

DOI: https://doi.org/10.1038/s41420-024-02271-1
Dev Neurobiol. 2025 Jan;85(1): e22957

Overexpression of Growth Differentiation Factor 15 Reduces Neuronal Cell Damage Induced by Oxygen-Glucose Deprivation/Reoxygenation via Inhibiting Endoplasmic Reticulum Stress-Mediated Ferroptosis.

Haiming Li, Bin Chen, Zhelin Chen, Jianming Luo, Binyuan Yang.

  Growth differentiation factor 15 (GDF15) can be induced under various stress conditions. This study aimed to explore the role of GDF15 in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced HT22 cells. OGD/R was employed to induce the HT22 cell model, and GDF15 expression was upregulated via transfection. Subsequently, the effects on inflammatory factors, oxidative stress markers, apoptosis-related proteins, and ferroptosis markers were detected. Relevant indicators were evaluated using techniques such as ELISA, probes, flow cytometry, and western blotting. Furthermore, changes in these phenotypes under the influence of the endoplasmic reticulum (ER) stress agonist tunicamycin (TM) were evaluated. The result showed that GDF15 was significantly up-regulated in OGD/R-treated HT22 cells. Overexpression of GDF15 significantly reduced the levels of inflammatory factors tumor necrosis factor-α, IL (interleukin)-1β, and IL-6, inhibited the production of reactive oxygen species and MDA, and improved activity of superoxide dismutase and GSH-Px. Flow cytometry and western blotting results showed that GDF15 overexpression significantly reduced cell apoptosis, reduced caspase3 activity, and regulated the expression of Bcl2 and Bax. In addition, overexpression of GDF15 reduces the levels of ferroptosis markers by inhibiting ER stress. ER stress inducer TM can reverse the protective effects of GDF15 overexpression and promote inflammation, oxidative stress, and apoptosis. This study shows that overexpression of GDF15 reduces OGD/R-induced HT22 cell damage, and ER stress-mediated ferroptosis is included in the regulatory mechanisms. This provides a theoretical basis for GDF15 as a new target for the treatment of cerebral ischemia-reperfusion injury.

Keywords:  ER stress; HT22; ferroptosis; growth differentiation factor; inflammation; ischemia‐reperfusion injury

DOI:  https://doi.org/10.1002/dneu.22957
Life Sci. 2024 Dec 22. pii: S0024-3205(24)00926-3. [Epub ahead of print] 123336

Poststroke hyperglycemia dysregulates cap-dependent translation in neural cells.

Pargol Tayefeh Ghahremani, Soha BaniArdalan, Parsa Alehossein, Arshi Parveen, Masoumeh Jorjani, Candice M Brown, Werner J Geldenhuys, Jason D Huber, Tauheed Ishrat, Sanaz Nasoohi.

   AIMS: Post stroke hyperglycemia has been shown to deter functional recovery. Earlier findings have indicated the cap-dependent translation regulator 4E-BP1 is detrimentally upregulated in hyperglycemic conditions. The present study aims to test the hypothesis that hyperglycemic ischemic reperfusion injury (I/R) affects normal protein translation poststroke.
METHODS: Rat primary cortical neurons (PCNs) were exposed to oxygen glucose deprivation (OGD) followed by increasing glucose concentration (0, 5, 10, 25 mM) at reoxygenation. In vivo, adult rats were subjected to two hours transient distal middle cerebral artery occlusion (t-dMCAO) and hyperglycemic reperfusion.
KEY FINDINGS: In PCN cultures, high glucose levels impaired normal neurite growth at 24 h I/R where it drastically depressed S6 ribosomal protein phosphorylation at serine 235/236 residues in 40S ribosomal subunit. This concurred with substantial hypoxia inducible factor-1α (HIF-1α) destabilization and sustained vascular endothelial growth factor (VEGF). Our immunoblotting findings indicated HIF-1α stabilization and AMPK activation rely on glucose availability. Incremental glucose concentrations above the physiological levels, induced a shift towards 4E-BP1, eIF-4E hypo-phosphorylated forms leading to reduced eIF-4E availability and efficacy, as the key to recruit the 40S ribosomal subunit to the 5' end of mRNA. In vivo, immunostaining of t-dMCAO rat brains showed remarkable decrease in phosphorylated 4E-BP1 and particularly s6 ribosomal protein in the marginal cortical tissue of hyperglycemic compared to normoglycemic animals.
SIGNIFICANCE: These findings suggest a remarkable association between hyperglycemic I/R injury with dysregulated cap-dependent translation poststroke. Further loss/gain of function experiment may elucidate the potential therapeutic targets in regulation of HIF-1α/translation in hyperglycemic I/R injury.

Keywords:  4E-BP1; Cap-dependent translation; Hyperglycemic ischemic reperfusion; eIF-4E

DOI:  https://doi.org/10.1016/j.lfs.2024.123336
FEBS J. 2024 Dec 22.

Hypoxia-induced translation of collagen-modifying enzymes PLOD2 and P4HA1 is dependent on RBM4 and eIF4E2 in human colon cancer HCT116 cells.

Hung-Hsuan Li, Hsin-Yuan Hung, Jau-Song Yu, Yu-Cheng Liao, Ming-Chih Lai.

  Hypoxia is a critical microenvironmental factor that induces tumorigenesis and cancer progression, including metastasis. The highly dynamic nature of the extracellular matrix (ECM) plays a crucial role in metastasis. Collagens are the predominant component of structural proteins embedded within the ECM. The biosynthesis of collagen typically undergoes a series of posttranslational modifications, such as hydroxylation of lysine and proline residues by procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) and prolyl 4-hydroxylases (P4Hs), respectively. Collagen hydroxylation is critical for ECM remodeling and maintenance. We recently investigated hypoxia-induced translation in human colon cancer HCT116 cells and identified several collagen-modifying enzymes, including procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) and prolyl 4-hydroxylase subunit alpha 1 (P4HA1). Although the translation of bulk mRNAs is repressed in hypoxia, specific mRNAs remain efficiently translated under such conditions. We have found that PLOD2 and P4HA1 are significantly upregulated in hypoxic HCT116 cells compared to normoxic cells. HIF-1 is known to induce the transcription of PLOD2 and P4HA1 during hypoxia. However, the molecular mechanisms of hypoxia-induced translation of PLOD2 and P4HA1 remain largely unclear. We provide evidence that RBM4 and eIF4E2 are required for hypoxia-induced translation of PLOD2 and P4HA1 mRNAs. The 3' UTRs of PLOD2 and P4HA1 mRNAs are involved in translational control during hypoxia in HCT116 cells.

Keywords:  collagen‐modifying enzymes; colorectal cancer; hypoxia; hypoxia‐induced translation; metastasis

DOI:  https://doi.org/10.1111/febs.17371
Diabet Med. 2024 Dec 24. e15456

Hypoglycaemic stimulation of macrophage cytokine release is suppressed by AMP-activated protein kinase activation.

Jiping Zhang, Alice E Pollard, Eleanor F Pearson, David Carling, Benoit Viollet, Kate L J Ellacott, Craig Beall.

   AIMS: Acute hypoglycaemia promotes pro-inflammatory cytokine production, increasing the risk for cardiovascular events in diabetes. AMP-activated protein kinase (AMPK) is regulated by and influences the production of pro-inflammatory cytokines. We sought to examine the mechanistic role of AMPK in low glucose-induced changes in the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF), which is elevated in people with diabetes.
METHODS: Macrophage cell line Raw264.7 cells, primary macrophage bone marrow-derived macrophages obtained from wild-type mice or AMPK γ1 gain-of-function mice, were used, as were AMPKα1/α2 knockout mouse embryonic fibroblasts (MEFs). Allosteric AMPK activators PF-06409577 and BI-9774 were used in conjunction with inhibitor SBI-0206965. We examined changes in protein phosphorylation/expression using western blotting and protein localisation using immunofluorescence. Metabolic function was assessed using extracellular flux analyses and luciferase-based ATP assay. Cytokine release was quantified by enzyme-linked immunosorbent assay (ELISA). Oxidative stress was detected using a fluorescence-based reactive oxygen species (ROS) assay, and cell viability was examined using flow cytometry.
RESULTS: Macrophages exposed to low glucose showed a transient and modest activation of AMPK and a metabolic shift towards increased oxidative phosphorylation. Moreover, low glucose increased oxidative stress and augmented the release of macrophage MIF. However, pharmacological activation of AMPK by PF-06409577 and BI-9774 attenuated low glucose-induced MIF release, with a similar trend noted with genetic activation using AMPKγ1 gain-of-function (D316A) mice, which produced a mild effect on low glucose-induced MIF release. Inhibition of NFĸB signalling diminished MIF release and AMPK activation modestly but significantly reduced low glucose-induced nuclear translocation of NFĸB.
CONCLUSIONS: Taken together, these data indicate that pharmacological AMPK activation suppresses the release of MIF from macrophages caused by energy stress, suggesting that AMPK activation could be a useful strategy for mitigating hypoglycaemia-induced inflammation.

Keywords:  AMP‐activated protein kinase; PF‐06409577; hypoglycaemia; inflammation; macrophage; macrophage migration inhibitory factor

DOI:  https://doi.org/10.1111/dme.15456
J Tehran Heart Cent. 2024 Jan;19(1): 6-13

The Role of Leukemia Inhibitory Factor in Cardiovascular Disease: Signaling in Inflammation, Coagulation, and Angiogenesis.

Hadi Rezaeeyan, Bahareh Moghimian-Boroujeni, Mehrnaz Abdolalian, Mohammadreza Javan.

   Background: Cardiovascular disease (CVD) is one of the principal causes of mortality in the world. Various factors have been identified in the pathogenesis of CVD. Leukemia inhibitory factor (LIF) as a secretory cytokine is one of these factors. The LIF receptor is located on endothelial cells and plays a role in the expression of specific genes in these cells. Endothelial cells are the innermost cells of blood vessels, and defects in these cells cause endothelial dysfunction and eventually CVD.
Methods: The present study is based on PubMed database information (1982-2022) using the following words: "cardiovascular disease," "endothelial cells," "leukemia inhibitory factor," and "angiogenesis."
Results: LIF can cause arteriosclerotic plaques by activating inflammatory mechanisms in monocytes through the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression. LIF can also induce vascular endothelial growth factor expression by activating signaling pathways, eventually leading to angiogenesis. Additionally, it can activate the coagulation cascade by factor VII production promotion within endothelial cells.
Conclusion: Understanding the interplay between LIF and the inflammation pathways, coagulation, and angiogenesis as key factors in CVD occurrence raises the possibility of targeting this factor as a potential strategy to mitigate CVD risk.

Keywords:  Angiogenesis; Cardiovascular disease; Endothelial cells; Leukemia inhibitory factor

DOI:  https://doi.org/10.18502/jthc.v19i1.15531
Life Sci. 2024 Dec 25. pii: S0024-3205(24)00929-9. [Epub ahead of print] 123339

GLP-1 and IL-6 regulates obesity in the gut and brain.

Kun Yang, Yu-Ting Wu, Yan He, Jin-Xiu Dai, Yu-Lu Luo, Jing-Hui Xie, Wei-Jun Ding.

  Obesity is a chronic metabolic disease characterized by excessive nutrient intake leading to increased subcutaneous or visceral fat, resulting in pathological and physiological changes. The incidence rate of obesity, an important form of metabolic syndrome, is increasing worldwide. Excess appetite is a key pathogenesis of obesity, and the inflammatory response induced by obesity has received increasing attention. This review focuses on the role of appetite-regulating factor (Glucogan-like peptide 1) and inflammatory factor (Interleukin-6) in the gut and brain in individuals with obesity and draws insights from the current literature.

Keywords:  Brain; Glucogan-like peptide 1; Gut; Interleukin-6; Obesity

DOI:  https://doi.org/10.1016/j.lfs.2024.123339
J Immunother Cancer. 2024 Dec 25. pii: e010040. [Epub ahead of print]12(12):

Lactylation-driven TNFR2 expression in regulatory T cells promotes the progression of malignant pleural effusion.

Qianqian Xue, Wenbei Peng, Siyu Zhang, Xiaoshan Wei, Linlin Ye, Zihao Wang, Xuan Xiang, Yao Liu, Haolei Wang, Qiong Zhou.

   BACKGROUND: Although tumor necrosis factor receptor 2 (TNFR2) has been recognized as an attractive next-generation candidate target for cancer immunotherapy, the factors that regulate the gene expression and their mechanistic effects on tumor-infiltrating regulatory T cells (Treg cells) remain poorly understood.
METHODS: Single-cell RNA sequencing analysis was employed to analyze the phenotypic and functional differences between TNFR2+ Treg cells and TNFR2- Treg cells. Malignant pleural effusion (MPE) from humans and mouse was used to investigate the potential mechanisms by which lactate regulates TNFR2 expression.
RESULTS: Treg cells with high TNFR2 expression exhibited elevated levels of immune checkpoint molecules. Additionally, the high expression of TNFR2 on Treg cells was positively correlated with a poor prognosis in MPE patients. Moreover, we revealed that lactate upregulated TNFR2 expression on Treg cells, thereby enhancing their immunosuppressive function in MPE. Mechanistically, lactate modulated the gene transcription of transcription factor nuclear factor-κB p65 (NF-κB p65) through histone H3K18 lactylation (H3K18la), subsequently upregulating the gene expression of TNFR2 and expediting the progression of MPE. Notably, lactate metabolism blockade combined with immune checkpoint blockade (ICB) therapy effectively enhanced the efficacy of ICB therapy, prolonged the survival time of MPE mice, and improved immunosuppression in the microenvironment of MPE.
CONCLUSIONS: The study explains the mechanism that regulates TNFR2 expression on Treg cells and its function in MPE progression, providing novel insights into the epigenetic regulation of tumor development and metabolic strategies for MPE treatment by targeting lactate metabolism in Treg cells.

Keywords:  Immunotherapy; Lung Cancer; T regulatory cell - Treg; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2024-010040
Front Pharmacol. 2024 ;15 1499414

NGF-mediated crosstalk: unraveling the influence of metabolic deregulation on the interplay between neural and pancreatic cancer cells and its impact on patient outcomes.

Francesca Trentini, Virginia Agnetti, Martina Manini, Elisa Giovannetti, Ingrid Garajová.

  Neural invasion is one of the most common routes of invasion in pancreatic cancer and it is responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Several molecules implicated in neural invasion are also responsible for pain onset including NGF belonging to the family of neutrophins. NGF released by cancer cells can sensitize sensory nerves which in turn results in severe pain. NGF receptors, TrkA and P75NTR, are expressed on both PDAC cells and nerves, strongly suggesting their role in neural invasion. The crosstalk between the nervous system and cancer cells has emerged as an important regulator of pancreatic cancer and its microenvironment. Nerve cells influence the pancreatic tumor microenvironment and these interactions are important for cancer metabolism reprogramming and tumor progression. In this review, we summarized the current knowledge on the interaction between nerves and pancreatic cancer cells and its impact on cancer metabolism.

Keywords:  NGF; metabolism; neural invasion; pain; pancreatic cancer

DOI:  https://doi.org/10.3389/fphar.2024.1499414
Clin Transl Oncol. 2024 Dec 25.

The evolving tumor-associated adipose tissue microenvironment in breast cancer: from cancer initiation to metastatic outgrowth.

Yang Yang, Xiao Ma, Yue Li, Lihua Jin, Xianchun Zhou.

  Adipocytes represent a significant proportion of breast tissue, comprising between 3.7 and 37% of stromal tissue. They play a pivotal role in metabolic regulation, energy supply, metabolic regulation, support effects, and cytokine release within the breast. In breast cancer (BC) tissue, adipocytes engage in intricate crosstalk with BC cells, playing a key role in tumor proliferation, invasion, metastasis formation, and metabolic remodeling. This is due to the provision of hormones, adipokines, and fatty acids to tumor cells by the adipocytes. With the initiation of metastatic outgrowth of BC, the peritumoral adipose tissue exhibits abundant and intricate changes based on its original construction and function, which convert it into a tumor-associated adipose tissue microenvironment (TAAME). It includes some specific adipocytes: adipose-derived stem cells (ASCs), cancer-associated adipocytes (CAAs), adipocyte-derived fibroblasts (ADFs), etc. From a mechanistic standpoint, specific adipocytes can facilitate the proliferation, invasion, metastasis, and angiogenesis of BC cells by secreting a multitude of cytokines (IL-6) and adipokines (leptin), which collectively create an environment conducive to BC progression. It is of paramount importance to recognize the TAAME as a crucial target for the diagnosis, treatment, and drug resistance of BC. Consequently, the review presents an overview of the characteristics and interactions of specific adipocytes within TAAME cell populations. This will facilitate the development of more effective personalized therapies against BC progression, relapse, and metastasis.

Keywords:  Adipocytes; Breast cancer; Metastasis; Progression; Tumor-associated adipose tissue microenvironment

DOI:  https://doi.org/10.1007/s12094-024-03831-8