Guido Kroemer’s research while affiliated with Cordeliers Research Centre, French Institute of Health and Medical Research and other places

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Publications (875)


Combining metformin and L-asparaginase strongly enhances apoptosis in DLBCL cell lines irrespective of their OxPhos or BCR/glycolytic subtypes. (A) Combination of metformin and L-asparaginase potentiates OxPhos and BCR/glycolytic DLBCL cell apoptosis. MD-901, OCI-LY19, and SU-DHL4 DLBCL cells were treated with the indicated antimetabolic drugs for 48 h and monitored for apoptosis by annexin V-PE and DAPI staining followed by FACS analysis. Error bars are means ± SD (n = 3). 0: control; M: metformin (2.5 mM); K: L-asparaginase (2 IU/mL). p values by unpaired Student t-test, ** p < 0.01; *** p < 0.001. (B) Combination of metformin and L-asparaginase potentiates loss of mitochondrial transmembrane potential (ΔΨm) in DLBCL cells. MD-901, OCI-LY19, and SU-DHL4 DLBCL cells were treated for 36 h with the indicated antimetabolic drugs. DLBCL cells were monitored for loss of mitochondrial transmembrane potential (ΔΨm) by TMRM staining followed by FACS analysis. 0: control; M: metformin (2.5 mM); K: L-asparaginase (2 IU/mL). Error bars represent means ± SD (n = 3). p values by unpaired Student t-test, ** p < 0.01; *** p < 0.001. (C–E) Whole cell extracts of MD-901, OCI-LY19, and SU-DHL4 DLBCL cells were treated as in (A) for the indicated periods of time and analyzed by immunoblotting for cleaved caspase 3 (C), cleaved PARP1 (D), and γ-H2AX (E). β-actin was also analyzed as loading control (n = 3). (F) Intracellular levels of glycolytic and mitochondrial ATP of MD-901, OCI-LY19, and SU-DHL4 DLBCL cells were measured as described in Materials and Methods. Error bars represent means ± SD (n = 4 individual experiments in duplicates). Original western blots are presented in File S1.
Metabolic alteration landscape of metformin and L-asparaginase combination in DLBCL cells. (A,B) L-asparaginase exerts dual asparaginase and glutaminase activities in DLBCL cells, strongly impacting glutaminolysis. Metabolic changes in MD-901, OCI-LY19, and SU-DHL4 DLBCL cells were monitored in the extracellular (A) and the intracellular (B) compartments using an untargeted NMR-based metabolomics approach following treatment for 24 h with metformin (M) (2.5 mM) and L-asparaginase (K) (2 IU/mL) either alone or in combination (MK). Boxplots of relative concentration of the indicated metabolites in the extracellular or intracellular compartments are shown, n = 10 per condition. Gln: glutamine; Asn: asparagine; Glu: glutamate; Asp: aspartate. (C) Glutamine, but not glucose deprivation, induces DLBCL cell death. MD-901, OCI-LY19, and SU-DHL4 DLBCL cells were cultured in either complete, glutamine-free, or glucose-free medium for 72 h, and cell death was assessed by trypan blue exclusion. Error bars represent means ± SD (n = 3). p values by unpaired Student t-test, **** p <0.0001. ns: non-significant. (D) L-asparaginase enhances DLBCL cell death under glutamine deprivation. DLBCL cells were cultured for 48 h in either complete medium or glutamine-free medium either in absence or presence of L-asparaginase (2 IU/mL). Cell death was assessed using trypan blue exclusion. Error bars represent means ± SD (n = 3). p values by unpaired Student t-test, * p < 0.05; *** p < 0.001; **** p <0.0001. (E) Combination of metformin and L-asparaginase impacts TCA cycle and antioxidant response. Metabolic changes were monitored as in (A). Boxplots of relative concentration of indicated metabolites in intracellular compartment are shown, n = 10 per condition. Fum: fumarate, GSH: glutathione. (F) Combination of metformin and L-asparaginase strongly impacts lipid metabolism. Metabolic changes were monitored as in (A). Boxplots of relative concentration of the indicated metabolites in the organic phase of the intracellular compartment are shown, n = 10 per condition. PL: phospholipid; TC: total cholesterol; GPC: glycerophosphocholine. (G) Schematic representation of the metabolic alteration landscape linked to mitochondrial metabolism upon metformin and L-asparaginase treatment in DLBCL cells.
Combination of metformin and L-asparaginase strongly inhibits glycolysis. (A) L-asparaginase inhibits glycolysis in DLBCL cells and counteracts the pro-glycolytic effect of metformin. Metabolic changes were monitored using an untargeted NMR-based metabolomics approach. Boxplots of relative concentration of the indicated metabolites in the extracellular or intracellular compartments are shown, n = 10 per condition. (B) Glucose limits the cytotoxic effect of metformin in DLBCL cells. DLBCL cells were cultured for 48 h in either complete medium (+ Glucose) or glucose-free medium (-Glucose) either in absence or presence of L-asparaginase (2 IU/mL). Cell death was assessed using trypan blue exclusion. Error bars represent means ± SD (n = 3). p values by unpaired Student t-test, ** p < 0.01; *** p < 0.001, **** p <0.0001. (C) Combination of metformin and L-asparaginase abolishes glucose-dependent pro-survival effect in DLBCL cells. DLBCL cells were cultured for 48 h in either complete medium or glucose-free medium either in absence or presence of combination of metformin (2.5 mM) and L-asparaginase (2 IU/mL). Cell death was assessed using trypan blue exclusion. Error bars represent means ± SD (n = 3). p values by unpaired Student t-test, ns: not significant. (D) Schematic representation of glycolysis alteration upon metformin and L-asparaginase treatment in DLBCL cells.
Metformin cooperates with L-asparaginase to modulate mTOR and MAPK signaling pathways. (A,B) Whole cell extracts of MD-901, OCI-LY19, and SU-DHL4 DLBCL cells were treated with metformin (M) (2.5 mM) and L-asparaginase (K) (2 IU/mL) either alone or in combination (MK) for the indicated periods of time and analyzed for (A) mTORC1 activity and (B) p38 and ERK MAPK pathways, using the indicated antibodies. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and β-actin were also analyzed as loading controls. The pathway diagrams were generated using BioRender (www.biorender.com). Original western blots are presented in File S1.
Combination of metformin and L-asparaginase has a clinical benefit in refractory/relapsed DLBCL patients. (A) Schematic representation of a four-week cycle of the optimized combined antimetabolic treatment. Metformin (M) and L-asparaginase (K, ®Kidrolase) were administered during the first two weeks, and the mTORC1 inhibitor temsirolimus (T, ®Torisel) in the subsequent two weeks. Specifically, L-asparaginase (10,000 IU) was administered on days 1, 3, 5, 7, 9, 11, and 13, and metformin (1000 mg/day) daily from day 1 to day 14. Temsirolimus (25 mg) was administered twice on days 14 and 21. (B) Reduced levels of glucose and glutamine, along with increased levels of glutamate in the serum of the three analyzed patients treated with the antimetabolic therapy after 4 h of co-administration of metformin and L-asparaginase. (C) Induction of apoptosis after 24 h of co-administration of metformin and L-asparaginase in one patient. (D) PET/CT analysis of one patient before and after 2 cycles of the antimetabolic treatment showing partial response with a reduction of 69% of total metabolic tumor volume (TMTV). (E) Response to treatment for the patient analyzed in (D). Duration of treatment under the antimetabolic treatment (dark blue). Duration of total survival after the treatment (light blue). The treatment stopped because of progression.
Metabolic Heterogeneity in Diffuse Large B-Cell Lymphoma Cells Reveals an Innovative Antimetabolic Combination Strategy
  • Article
  • Full-text available

January 2025

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26 Reads

Leonardo Lordello

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Karoline Kielbassa-Elkadi

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[...]

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Véronique Baud

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, characterized by aggressive and heterogeneous tumors originating from B-cells. Especially in patients with relapsed or refractory (R/R) disease, DLBCL remains a challenging cancer to treat. Metabolic reprogramming is a hallmark of malignant cells. Our research focuses on developing strategies to enhance clinical outcomes for R/R DLBCL patients by targeting metabolic vulnerabilities. Methods: We investigated the effects of combining metformin and L-asparaginase, two FDA-approved antimetabolic drugs, on DLBCL cell metabolism and survival. Nuclear magnetic resonance (NMR) spectroscopy was employed to assess metabolic disturbances induced by the drug combination. The impact on lipid metabolism, glycolysis, glutaminolysis, the tricarboxylic acid (TCA) cycle, and antioxidant responses was examined. Induction of apoptosis was evaluated by FACS analysis. Results: The combination of metformin and L-asparaginase strongly sensitized DLBCL cells to apoptosis, independently of their oxidative phosphorylation (OxPhos) or BCR/glycolytic status. NMR spectroscopy revealed that this combination induces broader metabolic disturbances than either drug alone. It disrupts lipid metabolism by altering levels of phospholipids, cholesterol, and fatty acids. Additionally, it counteracts the pro-glycolytic effect of metformin, decreases glycolysis, and reduces glutaminolysis. It also affects the TCA cycle and antioxidant responses, critical for cellular energy production and redox balance. Furthermore, this combination interferes with two key cancer survival pathways, mTORC1 and MAPK signaling. Importantly, proof of principle for its beneficial effect was demonstrated in DLBCL patients. Conclusions: Combining metformin and L-asparaginase affects DLBCL cell survival by targeting multiple metabolic pathways and may represent a novel therapeutic approach for R/R DLBCL patients.

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Fig. 1 Transcriptome and DNA methylome profiling of human breast cancer tissues. Workflow of the experimental design to identify tumor suppressor genes in breast cancer (BC) via RNA-sequencing and DNA methylation assays using non-tumor/normal and malignant breast tissue specimens extracting data from our (discovery) cohort of breast patients (a), or from TCGA dataset (b). a, b were created with BioRender.com. Volcano plots of differentially expressed genes (c, e), and differentially methylated genes (d, f) (reported according to their log 2 fold change and p-value in non-tumor/normal versus tumor breast samples), from our cohort of BC individuals (c, d) and from TCGA dataset (e, f). Of note, p-value ≤ 0.05 and |log 2 FC|≥ 1 for significant differentially expressed genes (c, e), and p-value ≤ 0.05 and |log 2 FC|≥ 0.5 for significant differentially methylated genes (d, f), were used as cut-off. Significant and insignificant modulations are in blue and grey, respectively. See Supplementary Tables S1-S5 for details. FC fold change; TCGA The Cancer Genome Atlas.
Fig. 3 Expression level of HOXA2 is a diagnostic and prognostic indicator in breast cancer. Diagnostic value of HOXA2 expression level in our cohort of breast samples (a), TCGA dataset (b), and METABRIC dataset (c, d) using two probe sets for HOXA2 transcript (c, probe set 1; d, probe set 2) through ROC curve analysis. e Representative immunohistochemistry images showing the staining of HOXA2 protein in human breast tissues (40x). From left to right panel: (i) high expression (more than 20% of positive cells), (ii) medium expression (from 1% to 20% of positive cells) and (iii) low expression (less than 1% of positive cells) of HOXA2 protein. f Graphical representation of the different expression levels of HOXA2 in 96 BC tissues obtained according to histological (G, grading) and clinical (T, tumor status and N, lymph node involvement) parameters. See Supplementary Table S13 for complementary data. Kaplan-Meier analysis of g OS, h RFS, and i DMFS in BC patients expressing high (red curves) versus low (black curves) levels of expression of HOXA2. Survival curves were generated with Kaplan-Meier Plotter online database. See Supplementary Table S14 for complementary data. Affymetrix HOXA2 ID: 214457_at. AUC area under the curve; BC breast cancer; DMFS distant metastasis-free survival; HR hazard ratio; METABRIC Molecular Taxonomy of Breast Cancer International Consortium; N lymph-node status; OS overall survival; Pr1 probe set 1; Pr2 Probe set 2; RFS relapse free-survival; ROC receiver operating characteristic; T tumor status; TCGA the cancer genome atlas.
Fig. 5 Depletion of HOXA2 enhances breast tumor growth. Cell proliferation (a, c) and migration (b, d) indexes of hTERT-HME1 HOXA2 knockout (HOXA2 KO ) or wild type (WT) cells (a, b), and of MCF7 cells transfected with pHOXA2 or pCMV (c, d), measured in real-time by xCELLigence ® system. a-d Graphs show mean ± SEM from one representative experiment. Statistical significance was assessed by Student's ttest. e-h Workflow of in vivo experimentation showing that hTERT-HME1 WT and HOXA2 KO cells were injected subcutaneously into the 4th abdominal mammary fat pad of NOD/SCID mice, and the development of the tumors was monitored over time (e: created with BioRender.com) (e). Tumor growth (f), size (g), and weight (h) at endpoint (n = 9/10 per group, mean ± SEM). f For comparing tumor growth curves, tumor growth p-values were calculated by means of a linear mixed-effect model modeling on the https://kroemerlab.shinyapps.io/ TumGrowth/ platform. g Four representative images per group of dissected tumors are shown. Scale bar 1 cm. HOXA2 KO , HOXA2 knockout cell line; WT wild type.
Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival

January 2025

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53 Reads

Cell Death and Differentiation

Accumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the Homeobox A2 ( HOXA2 ) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of HOXA2 in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of HOXA2 was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of HOXA2 and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of HOXA2 in human BC tissues. Low HOXA2 expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of HOXA2 expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic HOXA2 overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored HOXA2 expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of HOXA2 leaded to a concomitantly decreased expression of PPARγ and its target CIDEC , a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies HOXA2 as a novel prognosis-relevant tumor suppressor in the mammary gland.


Extracellular acyl-CoA-binding protein as an independent biomarker of COVID-19 disease severity

January 2025

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23 Reads

Background Factors leading to severe COVID-19 remain partially known. New biomarkers predicting COVID-19 severity that are also causally involved in disease pathogenesis could improve patient management and contribute to the development of innovative therapies. Autophagy, a cytosolic structure degradation pathway is involved in the maintenance of cellular homeostasis, degradation of intracellular pathogens and generation of energy for immune responses. Acyl-CoA binding protein (ACBP) is a key regulator of autophagy in the context of diabetes, obesity and anorexia. The objective of our work was to assess whether circulating ACBP levels are associated with COVID-19 severity, using proteomics data from the plasma of 903 COVID-19 patients. Methods Somalogic proteomic analysis was used to detect 5000 proteins in plasma samples collected between March 2020 and August 2021 from hospitalized participants in the province of Quebec, Canada. Plasma samples from 903 COVID-19 patients collected during their admission during acute phase of COVID-19 and 295 hospitalized controls were assessed leading to 1198 interpretable proteomic profiles. Levels of anti-SARS-CoV-2 IgG were measured by ELISA and a cell-binding assay. Results The median age of the participants was 59 years, 46% were female, 65% had comorbidities. Plasma ACBP levels correlated with COVID-19 severity, in association with inflammation and anti-SARS-CoV-2 antibody levels, independently of sex or the presence of comorbidities. Samples collected during the second COVID-19 wave in Quebec had higher levels of plasma ACBP than during the first wave. Plasma ACBP levels were negatively correlated with biomarkers of T and NK cell responses interferon-γ, tumor necrosis factor-α and interleukin-21, independently of age, sex, and severity. Conclusions Circulating ACBP levels can be considered a biomarker of COVID-19 severity linked to inflammation. The contribution of extracellular ACBP to immunometabolic responses during viral infection should be further studied.




AI-based classification of anticancer drugs reveals nucleolar condensation as a predictor of immunogenicity

December 2024

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39 Reads

Molecular Cancer

Background Immunogenic cell death (ICD) inducers are often identified in phenotypic screening campaigns by the release or surface exposure of various danger-associated molecular patterns (DAMPs) from malignant cells. This study aimed to streamline the identification of ICD inducers by leveraging cellular morphological correlates of ICD, specifically the condensation of nucleoli (CON). Methods We applied artificial intelligence (AI)-based imaging analyses to Cell Paint-stained cells exposed to drug libraries, identifying CON as a marker for ICD. CON was characterized using SYTO 14 fluorescent staining and holotomographic microscopy, and visualized by AI-deconvoluted transmitted light microscopy. A neural network-based quantitative structure-activity relationship (QSAR) model was trained to link molecular descriptors of compounds to the CON phenotype, and the classifier was validated using an independent dataset from the NCI-curated mechanistic collection of anticancer agents. Results CON strongly correlated with the inhibition of DNA-to-RNA transcription. Cytotoxic drugs that inhibit RNA synthesis without causing DNA damage were as effective as conventional cytotoxicants in inducing ICD, as demonstrated by DAMPs release/exposure and vaccination efficacy in mice. The QSAR classifier successfully predicted drugs with a high likelihood of inducing CON. Conclusions We developed AI-based algorithms for predicting CON-inducing drugs based on molecular descriptors and their validation using automated micrographs analysis, offering a new approach for screening ICD inducers with minimized adverse effects in cancer therapy.


Overview of thematic discussions on optimizing radiotherapy-immunotherapy combination strategies at the immunorad Conference.
Overview of the technological innovations in the field of precision oncology and personalized medicine presented and discussed at immunorad Conference.
of the advances presented at immunorad conference likely to change the paradigms of radiotherapy in the future.
Pushing the boundaries of radiotherapy-immunotherapy combinations: highlights from the 7 immunorad conference

December 2024

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117 Reads

Over the last decade, the annual Immunorad Conference, held under the joint auspicies of Gustave Roussy (Villejuif, France) and the Weill Cornell Medical College (New-York, USA) has aimed at exploring the latest advancements in the fields of tumor immunology and radiotherapy-immunotherapy combinations for the treatment of cancer. Gathering medical oncologists, radiation oncologists, physicians and researchers with esteemed expertise in these fields, the Immunorad Conference bridges the gap between preclinical outcomes and clinical opportunities. Thus, it paves a promising way toward optimizing radiotherapy-immunotherapy combinations and, from a broader perspective, improving therapeutic strategies for patients with cancer. Herein, we report on the topics developed by key-opinion leaders during the 7th Immunorad Conference held in Paris-Les Cordeliers (France) from September 27th to 29th 2023, and set the stage for the 8th edition of Immunorad which will be held at Weill Cornell Medical College (New-York, USA) in October 2024.


Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death

December 2024

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39 Reads

Cholesterol serves as a vital lipid that regulates numerous physiological processes. Nonetheless, its role in regulating cell death processes remains incompletely understood. In this study, we investigated the role of cholesterol trafficking in immunogenic cell death. Through cell-based drug screening, we identified two antidepressants, sertraline and indatraline, as potent inducers of the nuclear translocation of TFEB (transcription factor EB). Activation of TFEB was mediated through the autophagy-independent lipidation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). Both compounds promoted cholesterol accumulation within lysosomes, resulting in lysosomal membrane permeabilization, disruption of autophagy and cell death that could be reversed by cholesterol depletion. Molecular docking analysis indicated that sertraline and indatraline have the potential to inhibit cholesterol binding to the lysosomal cholesterol transporters, NPC1 (NPC intracellular cholesterol transporter 1) and NPC2. This inhibitory effect might be further enhanced by the upregulation of NPC1 and NPC2 expression by TFEB. Both antidepressants also upregulated PLA2G15 (phospholipase A2 group XV), an enzyme that elevates lysosomal cholesterol. In cancer cells, sertraline and indatraline elicited immunogenic cell death, converting dying cells into prophylactic vaccines that were able to confer protection against tumor growth in mice. In a therapeutic setting, a single dose of each compound was sufficient to significantly reduce the outgrowth of established tumors in a T-cell-dependent manner. These results identify sertraline and indatraline as immunostimulatory agents for cancer treatment. More generally, this research shed light on novel therapeutic avenues harnessing lysosomal cholesterol transport to regulate immunogenic cell death.Abbreviation: ATG5: autophagy related 5; ATG13: autophagy related 13; DKO: double knockout; ICD: immunogenic cell death; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LGALS3: galectin 3; LDL: low-density lipoprotein; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTX: mitoxantrone; NPC1: NPC intracellular cholesterol transporter 1; NPC2: NPC intracellular cholesterol transporter 2; TFE3: transcription factor E3; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.


SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition

December 2024

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13 Reads

Science Advances

Direct targeting of the KRAS-G12C –mutant protein using covalent inhibitors (G12Ci) acts on human non–small cell lung cancer (NSCLC). However, drug resistance is an emerging concern in this approach. Here, we show that MRTX849, a covalent inhibitor targeting the KRAS-G12C mutation, leads to the reactivation of the mitogen-activated protein kinase signaling pathway in MRTX849-resistant NSCLC and pancreatic ductal adenocarcinoma. A genome-wide CRISPR screen revealed that the adenosine triphosphate binding cassette transporter ABCC1 mediates MRTX849 resistance. Functional studies demonstrated that the transcription factor JUN drives ABCC1 expression, resulting in multidrug resistance. An unbiased drug screen identified the tyrosine kinase inhibitor dasatinib that potentiates MRTX849 efficacy by inhibiting SRC-dependent JUN activation, avoiding multidrug resistance and tumor suppression in vitro as well as in suitable preclinical mouse models and patient-derived organoids. SRC inhibitors (DGY-06-116, dasatinib, and bosutinib) also exhibit synergistic effects with MRTX849 in eliminating various tumor cell lines carrying KRAS-G12C mutations. Thus, SRC inhibitors amplify the therapeutic utility of G12Ci.


Autophagy-dependent hepatocyte secretion of DBI/ACBP induced by glucocorticoids determines the pathogenesis of Cushing syndrome

December 2024

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14 Reads

DBI/ACBP is a phylogenetically ancient hormone that stimulates appetite and lipo-anabolism. In response to starvation, DBI/ACBP is secreted through a noncanonical, macroautophagy/autophagy-dependent pathway. The physiological hunger reflex involves starvation-induced secretion of DBI/ACBP from multiple cell types. DBI/ACBP concentrations subsequently increase in extracellular fluids to stimulate food intake. Recently, we observed that glucocorticoids, which are endogenous stress hormones as well as anti-inflammatory drugs, upregulate DBI/ACBP expression at the transcriptional level and stimulate autophagy in hepatocytes, thereby causing a surge in circulating DBI/ACBP levels. Prolonged increase in glucocorticoid concentrations causes an extreme form of metabolic syndrome, dubbed "Cushing syndrome", which is characterized by clinical features including hyperphagia, hyperdipsia, dyslipidemia, hyperinsulinemia, insulin resistance, lipodystrophy, visceral adiposity, steatosis, sarcopenia and osteoporosis. Mice and patients with Cushing syndrome exhibit supraphysiological DBI/ACBP plasma levels. Of note, neutralization of extracellular DBI/ACBP protein with antibodies or mutation of the DBI/ACBP receptor (i.e. the GABRG2 subunit of GABR [gamma-aminobutyric acid type A receptor]) renders mice resistant to the induction of Cushing syndrome. Similarly, knockout of Dbi/Acbp in hepatocytes suppresses the corticotherapy-induced surge in plasma DBI/ACBP concentrations and prevents the manifestation of most of the characteristics of Cushing syndrome. We conclude that autophagy-mediated secretion of DBI/ACBP by hepatocytes constitutes a critical step of the pathomechanism of Cushing syndrome. It is tempting to speculate that stress-induced chronic elevations of endogenous glucocorticoids also compromise human health due to the protracted augmentation of circulating DBI/ACBP concentrations.


Citations (47)


... However, despite the existing research, there remains a scarcity of large-scale clinical trials conclusively demonstrating the link between PCSK9 inhibition and metabolic disorders such as obesity, overweight, and hypertension. In addition, there have been relevant studies on PCSK9 inhibition in sepsis [81], viral infections [82], and cancer [83], but the specific mechanisms are still unclear. ...

Reference:

Pleiotropic Effects of PCSK9 Inhibitors on Cardio-Cerebrovascular Diseases
PCSK9 in metabolism and diseases
  • Citing Article
  • November 2024

Metabolism

... Patients were also assessed for concurrent exposure to other medications, including BZDs in 36% of cases. Consistent with our results, the authors reported that generic BZD intake was associated with not significant trends toward worse PFS and OS [32]. Recently Montégut et al. [33] provided valuable insights in this regard. ...

Benzodiazepines compromise the outcome of cancer immunotherapy

... These patients received a one-time FMT after laxative bowel cleaning from one of 11 healthy donors, after which NSCLC patients were treated with dual immunotherapy. In the NSCLC group, no patients achieved CR, although 15 patients exhibited PR and 3 SD [45]. Data on FMT is summarized in Table 3. Sign "/" = correct information is not provided or is not valid. ...

1068P Phase II trial of fecal microbiota transplantation (FMT) plus immune checkpoint inhibition (ICI) in advanced non-small cell lung cancer and cutaneous melanoma (FMT-LUMINate)
  • Citing Article
  • September 2024

Annals of Oncology

... High circulating ACBP levels have been observed in the context of aging and obesity (15,(17)(18)(19). Moreover, elevated plasma ACBP levels have been documented in patients at risk of developing cardiovascular diseases (20) and cancer (21). ...

Acyl-coenzyme a binding protein (ACBP) - a risk factor for cancer diagnosis and an inhibitor of immunosurveillance

Molecular Cancer

... Mechanistically, it is plausible to speculate that CR protects from HFpEF, at least in part, through autophagy induction because autophagy-related genes and proteins are downregulated in humans and rodents with HFpEF, respectively [34,39,135,136]. In support of this assumption, CR improved diastolic dysfunction, coinciding with suppressed mTOR and increased ratio of LC3B-II/LC3B-I (microtubule-associated protein 1 light chain 3B) in aged rats [137]. ...

Anti-ageing interventions for the treatment of cardiovascular disease
  • Citing Article
  • August 2024

Cardiovascular Research

... Moreover, whether the murine system can properly model ICD induction in human cancer cells as well as whether systemic factors may influence immune fitness in patients with cancer remains to be formally established lesions in the same patient or even across different areas of the same tumor, on an individual basis may offer actionable mechanistic insights to develop superior combinations of ICD inducers and ICIs. Sixth, a number of variables affecting patient immune fitness may prevent ICD inducers from actually eliciting an ICI-active immune response, including (1) polymorphisms in genes encoding critical immune receptors [141], (2) alterations in the gut or intratumoral microbiome [142], (3) dietary habits [143], (4) comorbidities [144], and (5) medications and over-the-counter drugs [115,145,146]. Upon precise identification, many of these barriers may offer a means to (1) select patients at increased likelihood to benefit from therapeutic regimens involving ICDinducing agents and ICIs and/or (2) improve the efficacy of such combinatorial strategies. ...

Long-distance microbial mechanisms impacting cancer immunosurveillance
  • Citing Article
  • August 2024

Immunity

... Furthermore, it is anticipated that by the year 2040, the incidence of new cases and mortality rates related to CRC will escalate to 3.2 million and 1.6 million, respectively (Sung et al. 2021;Morgan et al. 2023). The emergence of CRC is intricately linked to a multitude of factors, encompassing age, body weight, dietary patterns, gender, ethnicity, and physical activity levels (Siegel et al. 2023;Gonzalez-Gutierrez et al. 2024). ...

Obesity-Associated Colorectal Cancer

International Journal of Molecular Sciences

... Examples include Actc1, which encodes cardiac muscle alpha-actin, and Casq1, which serves as the primary calcium-binding protein in the sarcoplasmic reticulum of skeletal muscle. Interestingly, spermidine biosynthesis-related genes Amd1 and Smox are highly induced, and spermidine is a known longevity molecule that promotes autophagy (Hofer et al. 2024). ...

Spermidine is essential for fasting-mediated autophagy and longevity

Nature Cell Biology