bims-stacyt 2024-01-14 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–01–14
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

S6K1 deficiency in tumor stroma impairs lung metastasis of melanoma in mice.
ONC201/TIC10 plus TLY012 anti-cancer effects via apoptosis inhibitor downregulation, stimulation of integrated stress response and death receptor DR5 in gastric adenocarcinoma.
O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4.
AMPK-mTORC1 pathway mediates hepatic IGFBP-1 phosphorylation in glucose deprivation.
Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
Propionate functions as a feeding-state-dependent regulatory metabolite to counter pro-inflammatory signaling linked to nutrient load and obesity.
Resveratrol attenuates high glucose-induced inflammation and improves glucose metabolism in HepG2 cells.

Biochem Biophys Res Commun. 2024 Jan 04. pii: S0006-291X(24)00002-0. [Epub ahead of print]696 149469

S6K1 deficiency in tumor stroma impairs lung metastasis of melanoma in mice.

Da-Eun Kim, Hyun-Soo Roh, Ga-Hee Kim, Dong Ha Bhang, Sung Hee Um, Rohit Singh, Kwan-Hyuck Baek.

  Accumulating data suggest that ribosomal protein S6 kinase 1 (S6K1), an effector in the mammalian target of rapamycin (mTOR) pathway, plays pleiotropic roles in tumor progression. However, to date, while the tumorigenic function of S6K1 in tumor cells has been well elucidated, its role in the tumor stroma remains poorly understood. We recently showed that S6K1 mediates vascular endothelial growth factor A (VEGF-A) production in macrophages, thereby supporting tumor angiogenesis and growth. As macrophage-derived VEGF-A is crucial for both tumor cell intravasation and extravasation across the vascular endothelium, our previous findings suggest that stromal S6K1 signaling is required for tumor metastatic spread. Therefore, we aimed to determine the impact of host S6K1 depletion on tumor metastasis using a murine model of pulmonary metastasis (S6k1-/- mice implanted with B16F10 melanoma). The ablation of S6K1 in the host microenvironment significantly reduced the metastasized B16F10 melanoma cells on the lung surface in both spontaneous and intravenous lung metastasis mouse models without affecting the incidence of metastasis to distant lymph nodes. In addition, stromal S6K1 loss decreased the number of tumor cells circulating in the peripheral blood of mice bearing B16F10 xenografts without affecting the vascular leakage induced by VEGF-A in vivo. These observations demonstrate that S6K1 signaling in host cells other than endothelial cells is required to modulate the host microenvironment to facilitate the metastatic spread of tumors via blood circulation, thus revealing its novel role in the tumor stroma during tumor progression.

Keywords:  Macrophage; Metastasis; S6K1; Tumor stroma; VEGF-A

DOI:  https://doi.org/10.1016/j.bbrc.2024.149469
Am J Cancer Res. 2023 ;13(12): 6290-6312

ONC201/TIC10 plus TLY012 anti-cancer effects via apoptosis inhibitor downregulation, stimulation of integrated stress response and death receptor DR5 in gastric adenocarcinoma.

Cassandra S Parker, Lanlan Zhou, Varun V Prabhu, Seulki Lee, Thomas J Miner, Eric A Ross, Wafik S El-Deiry.

Gastric adenocarcinoma typically presents with advanced stage when inoperable. Chemotherapy options include non-targeted and toxic agents, leading to poor 5-year patient survival outcomes. Small molecule ONC201/TIC10 (TRAIL-Inducing Compound #10) induces cancer cell death via ClpP-dependent activation of the integrated stress response (ISR) and up-regulation of the TRAIL pathway. We previously found in breast cancer, pancreatic cancer and endometrial cancer that ONC201 primes tumor cells for TRAIL-mediated cell death through ISR-dependent upregulation of ATF4, CHOP and TRAIL death receptor DR5. We investigated the ability of ONC201 to induce apoptosis in gastric adenocarcinoma cells in combination with recombinant human TRAIL (rhTRAIL) or PEGylated trimeric TRAIL (TLY012). AGS (caspase 8-, KRAS-, PIK3CA-mutant, HER2-amplified), SNU-1 (KRAS-, MLH1-mutant, microsatellite unstable), SNU-5 (p53-mutant) and SNU-16 (p53-mutant) gastric adenocarcinoma cells were treated with ONC201 and TRAIL both in cell culture and in vivo. Gastric cancer cells showed synergy following dual therapy with ONC201 and rhTRAIL/TLY012 (combination indices < 0.6 at doses that were non-toxic towards normal fibroblasts). Synergy was observed with increased cells in the sub-G1 phase of the cell cycle with dual ONC201 plus TRAIL therapy. Increased PARP, caspase 8 and caspase 3 cleavage after ONC201 plus TRAIL further documented apoptosis. Increased cell surface expression of DR5 with ONC201 therapy was observed by flow cytometry, and immunoblotting revealed ONC201 upregulation of the ISR, ATF4, and CHOP. We observed downregulation of anti-apoptotic cIAP-1 and XIAP in all cells except AGS, and cFLIP in all cells except SNU-16. We tested the regimen in an organoid model of human gastric cancer, and in murine sub-cutaneous xenografts using AGS and SNU-1 cells. Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.

Keywords: ATF4; CHOP; DR5; ISR; ONC201; TRAIL; XIAP; cIAP1; gastric cancer; imipridone; integrated stress response
Front Aging Neurosci. 2023 ;15 1326127

O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4.

Ibtihal M Alghusen, Marisa S Carman, Heather Wilkins, Sophiya John Ephrame, Amy Qiang, Wagner B Dias, Halyna Fedosyuk, Aspin R Denson, Russell H Swerdlow, Chad Slawson.

   Background: Accumulation of mitochondrial dysfunctional is a hallmark of age-related neurodegeneration including Alzheimer's disease (AD). Impairment of mitochondrial quality control mechanisms leading to the accumulation of damaged mitochondria and increasing neuronal stress. Therefore, investigating the basic mechanisms of how mitochondrial homeostasis is regulated is essential. Herein, we investigate the role of O-GlcNAcylation, a single sugar post-translational modification, in controlling mitochondrial stress-induced transcription factor Activating Transcription Factor 4 (ATF4). Mitochondrial dysfunction triggers the integrated stress response (ISRmt), in which the phosphorylation of eukaryotic translation initiation factor 2α results in the translation of ATF4.
Methods: We used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma and HeLa cell-lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) on ISRmt using biochemical analyses.
Results: We show that TMG elevates ATF4 protein levels upon mitochondrial stress in SH-SY5Y neuroblastoma and HeLa cell-lines. An indirect downstream target of ATF4 mitochondrial chaperone glucose-regulated protein 75 (GRP75) is significantly elevated. Interestingly, knock-down of O-GlcNAc transferase (OGT), the enzyme that adds O-GlcNAc, in SH-SY5Y increases ATF4 protein and mRNA expression. Additionally, ATF4 target gene Activating Transcription Factor 5 (ATF5) is significantly elevated at both the protein and mRNA level. Brains isolated from TMG treated mice show elevated levels of ATF4 and GRP75. Importantly, ATF4 occupancy increases at the ATF5 promoter site in brains isolated from TMG treated mice suggesting that O-GlcNAc is regulating ATF4 targeted gene expression. Interestingly, ATF4 and GRP75 are not induced in TMG treated familial Alzheimer's Disease mice model. The same results are seen in a human in vitro model of AD.
Conclusion: Together, these results indicate that in healthy conditions, O-GlcNAc regulates the ISRmt through regulating ATF4, while manipulating O-GlcNAc in AD has no effect on ISRmt.

Keywords:  Alzheimer’s disease; O-GlcNAc; activating transcription factor 4 (ATF4); integrated stress response; mitochondrial stress

DOI:  https://doi.org/10.3389/fnagi.2023.1326127
J Mol Endocrinol. 2024 Jan 01. pii: JME-23-0137. [Epub ahead of print]

AMPK-mTORC1 pathway mediates hepatic IGFBP-1 phosphorylation in glucose deprivation.

Jenica H Kakadia, Muhammad U Khalid, Ilka U Heinemann, Victor Han.

Mechanisms underlying limitations in glucose supply that restrict fetal growth are not well established. IGF-1 is an important regulator of fetal growth and IGF-1 bioavailability is markedly inhibited by IGFBP-1 especially when the binding protein is hyperphosphorylated. We hypothesized that the AMPK-mTORC1 pathway increases IGFBP-1 phosphorylation in response to glucose deprivation. Glucose deprivation in HepG2 cells activated AMPK and TSC2, inhibited mTORC1 and increased IGFBP-1 secretion and site-specific phosphorylation. Glucose deprivation also decreased IGF-1 bioavailability and IGF-dependent activation of IGF-1R. AICAR (an AMPK-activator) activated TSC2, inhibited mTORC1 and increased IGFBP-1 secretion/ phosphorylation. Further, siRNA silencing of either AMPK or TSC2 prevented mTORC1 inhibition and IGFBP-1 secretion and phosphorylation in glucose deprivation. Our data suggest that the increase in IGFBP-1 phosphorylation in response to glucose deprivation is mediated by the activation of AMPK/TSC2 and inhibition of mTORC1, providing a possible mechanistic link between glucose deprivation and restricted fetal growth.

DOI: https://doi.org/10.1530/JME-23-0137
EMBO J. 2024 Jan 11.

Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.

Ching-Fang Chang, Amanda L Gunawan, Irene Liparulo, Peter-James H Zushin, Kaitlyn Vitangcol, Greg A Timblin, Kaoru Saijo, Biao Wang, Güneş Parlakgül, Ana Paula Arruda, Andreas Stahl.

  Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.

Keywords:  Brown Adipose Tissue; Coenzyme Q; FGF21; Mitochondrial Unfolded Protein Response; Mitohormesis

DOI:  https://doi.org/10.1038/s44318-023-00008-x
J Leukoc Biol. 2024 Jan 11. pii: qiae006. [Epub ahead of print]

Propionate functions as a feeding-state-dependent regulatory metabolite to counter pro-inflammatory signaling linked to nutrient load and obesity.

Kim Han, Allison M Meadows, Matthew J Rodman, Anna Chiara Russo, Rahul Sharma, Komudi Singh, Shahin Hassanzadeh, Pradeep K Dagur, Rebecca D Huffstutler, Fynn N Krause, Julian L Griffin, Yvonne Baumer, Tiffany M Powell-Wiley, Michael N Sack.

  Generally, fasting and refeeding confer anti- and pro-inflammatory effects, respectively. In humans, these caloric-load interventions function, in part, via regulation of CD4+ T cell biology. However, mechanisms orchestrating this regulation remain incomplete. We employed integrative bioinformatics of RNA-seq and HPLC-mass spectrometry data to measure serum metabolites and gene expression of peripheral blood mononuclear cells isolated from fasting and refeeding in volunteers to identify nutrient-load metabolite-driven immunoregulation. Propionate, a short chain fatty acid (SCFA), and the SCFA-sensing G-protein coupled receptor (GPCR) 43 (ffar2) were co-ordinately and inversely regulated by fasting and refeeding. Propionate and FFAR agonists decreased IFNγ and IL-17 and significantly blunted HDAC activity in CD4+ T cells. Furthermore, propionate blunted NFκB activity and diminished IL-6 release. In parallel, propionate reduced phosphorylation of canonical TH1 and TH17 regulators, STAT1 and STAT3, respectively. Conversely, knockdown of FFARs significantly attenuated the anti-inflammatory role of propionate. Interestingly, propionate recapitulated the blunting of CD4+ T helper cell activation in primary cells from obese individuals, extending the role of this metabolite to a disease associated with low-grade inflammation. Together, these data identify a nutrient-load responsive SCFA-GPCR linked pathway to regulate CD4+ helper T cell immune responsiveness.

Keywords:  CD4+ T cells; FFAR2; Fasting; IL-6; Metabolite; NFκB; Propionate

DOI:  https://doi.org/10.1093/jleuko/qiae006
Sci Rep. 2024 Jan 11. 14(1): 1106

Resveratrol attenuates high glucose-induced inflammation and improves glucose metabolism in HepG2 cells.

Abegail Mukhethwa Tshivhase, Tandi Matsha, Shanel Raghubeer.

Diabetes mellitus (DM) is characterized by impaired glucose and insulin metabolism, resulting in chronic hyperglycemia. Hyperglycemia-induced inflammation is linked to the onset and progression of diabetes. Resveratrol (RES), a polyphenol phytoalexin, is studied in diabetes therapeutics research. This study evaluates the effect of RES on inflammation and glucose metabolism in HepG2 cells exposed to high glucose. Inflammation and glucose metabolism-related genes were investigated using qPCR. Further, inflammatory genes were analyzed by applying ELISA and Bioplex assays. High glucose significantly increases IKK-α, IKB-α, and NF-kB expression compared to controls. Increased NF-kB expression was followed by increased expression of pro-inflammatory cytokines, such as TNF-α, IL-6, IL-β, and COX2. RES treatment significantly reduced the expression of NF-kB, IKK-α, and IKB-α, as well as pro-inflammatory cytokines. High glucose levels reduced the expression of TGFβ1, while treatment with RES increased the expression of TGFβ1. As glucose levels increased, PEPCK expression was reduced, and GCK expression was increased in HepG2 cells treated with RES. Further, HepG2 cells cultured with high glucose showed significant increases in KLF7 and HIF1A but decreased SIRT1. Moreover, RES significantly increased SIRT1 expression and reduced KLF7 and HIF1A expression levels. Our results indicated that RES could attenuate high glucose-induced inflammation and enhance glucose metabolism in HepG2 cells.

DOI: https://doi.org/10.1038/s41598-023-50084-6