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2.
EMBO Rep ; 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38907027

ABSTRACT

Extracellular matrix (ECM) is a major component of the tumor environment, promoting the establishment of a pro-invasive behavior. Such environment is supported by both tumor- and stromal-derived metabolites, particularly lactate. In prostate cancer (PCa), cancer-associated fibroblasts (CAFs) are major contributors of secreted lactate, able to impact on metabolic and transcriptional regulation in cancer cells. Here, we describe a mechanism by which CAF-secreted lactate promotes in PCa cells the expression of genes coding for the collagen family. Lactate-exploiting PCa cells rely on increased α-ketoglutarate (α-KG) which activates the α-KG-dependent collagen prolyl-4-hydroxylase (P4HA1) to support collagen hydroxylation. De novo synthetized collagen plays a signaling role by activating discoidin domain receptor 1 (DDR1), supporting stem-like and invasive features of PCa cells. Inhibition of lactate-induced collagen hydroxylation and DDR1 activation reduces the metastatic colonization of PCa cells. Overall, these results provide a new understanding of the link between collagen remodeling/signaling and the nutrient environment exploited by PCa.

3.
EMBO Mol Med ; 2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38926633

ABSTRACT

Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.

4.
Sci Transl Med ; 16(736): eadf9874, 2024 Feb 28.
Article in English | MEDLINE | ID: mdl-38416843

ABSTRACT

Targeting aromatase deprives ER+ breast cancers of estrogens and is an effective therapeutic approach for these tumors. However, drug resistance is an unmet clinical need. Lipidomic analysis of long-term estrogen-deprived (LTED) ER+ breast cancer cells, a model of aromatase inhibitor resistance, revealed enhanced intracellular lipid storage. Functional metabolic analysis showed that lipid droplets together with peroxisomes, which we showed to be enriched and active in the LTED cells, controlled redox homeostasis and conferred metabolic adaptability to the resistant tumors. This reprogramming was controlled by acetyl-CoA-carboxylase-1 (ACC1), whose targeting selectively impaired LTED survival. However, the addition of branched- and very long-chain fatty acids reverted ACC1 inhibition, a process that was mediated by peroxisome function and redox homeostasis. The therapeutic relevance of these findings was validated in aromatase inhibitor-treated patient-derived samples. Last, targeting ACC1 reduced tumor growth of resistant patient-derived xenografts, thus identifying a targetable hub to combat the acquisition of estrogen independence in ER+ breast cancers.


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/pathology , Aromatase Inhibitors/pharmacology , Aromatase Inhibitors/therapeutic use , Peroxisomes/metabolism , Peroxisomes/pathology , Acetyl-CoA Carboxylase , Lipid Droplets/metabolism , Lipid Droplets/pathology , Cell Line, Tumor , Estrogens/metabolism , Drug Resistance, Neoplasm
5.
Acta Biomed ; 94(5): e2023234, 2023 10 17.
Article in English | MEDLINE | ID: mdl-37850765

ABSTRACT

BACKGROUND AND AIM: Current data suggest little to no possibility of original COVID-19 transmission in pregnant women to the fetus during pregnancy or childbirth. Warning with Omicron new variants has decreased. CASE REPORT: A clinical case of a SARS-CoV-2 virus transplacental infection of a newborn, born at the end of 2022, from a mother who tested positive for Sars-covid-2 and positive IgM SARS-CoV-2 anti-virus. The newborn tested positive for SARS-CoV-2 12 hours after birth, and was clinically symptomatic after three days, an increase in IgM antibodies was not found, although the virus was identified in the urine samples through molecular tests. The insufficient time to determine the presence of antibodies and the immune system's state of immaturity can explain the lack of IgM in the newborn's blood at 14 days after birth. CONCLUSIONS: The Omicron SARS-CoV-2 keeps provoking infections among newborns, especially if the mother contracts it during the third trimester. The host response is most likely influenced by the newborn's peculiar state of immune immaturity. Just before birth, a positive nasal swab and the presence of a positive urine examination confirmed the diagnosis of intraplacental exposure. Research on the virus through molecular tests of urines can represent an additional technique when an aetiological framework of the infection is necessary and a distinction between congenital and post-natal forms.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Infant, Newborn , Female , Pregnancy , Humans , SARS-CoV-2 , Pregnancy Complications, Infectious/diagnosis , Infectious Disease Transmission, Vertical , Immunoglobulin M
6.
Mol Cell Biochem ; 478(11): 2405-2407, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37776408
7.
Acta Biomed ; 94(3): e2023098, 2023 06 14.
Article in English | MEDLINE | ID: mdl-37326274

ABSTRACT

BACKGROUND AND AIM: Vitamin A toxicity is uncommon, but when it occurs can be serious and even fatal. A case vitamin A intoxication with high levels in liver tests, thrombocytopenia and appearance virosis. Laboratory testing is one of the most widely used diagnostic interventions supporting medical decisions of this phenomenon are necessary. CASE REPORT: Here, we report a case vitamin A intoxication with high levels in liver tests, thrombocytopenia and appearance virosis. The patient showed several clinical signs abdominal pain, including mild anemia and thrombocytopenia. CONCLUSIONS: We believe that Laboratory testing is one of the most widely used diagnostic interventions supporting medical decisions, and further investigations regarding the etiology and prevalence of this phenomenon are necessary. (www.actabiomedica.it).


Subject(s)
Anemia , Hypervitaminosis A , Thrombocytopenia , Humans , Hypervitaminosis A/complications , Hypervitaminosis A/diagnosis , Vitamin A , Anemia/etiology , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis
9.
FEBS Lett ; 596(18): 2364-2381, 2022 09.
Article in English | MEDLINE | ID: mdl-35776088

ABSTRACT

Deregulated metabolism is a well-known feature of several challenging diseases, including diabetes, obesity and cancer. Besides their important role as intracellular bioenergetic molecules, dietary nutrients and metabolic intermediates are released in the extracellular environment. As such, they may achieve unconventional roles as hormone-like molecules by activating cell surface G-protein-coupled receptors (GPCRs) that regulate several pathophysiological processes. In this review, we provide an insight into the role of lactate, succinate, fatty acids, amino acids as well as ketogenesis-derived and ß-oxidation-derived intermediates as extracellular signalling molecules. Moreover, the mechanisms by which their cognate metabolite-sensing GPCRs integrate nutritional and metabolic signals with specific intracellular pathways will be described. A better comprehension of these aspects is of fundamental importance to identify GPCRs as novel druggable targets.


Subject(s)
Amino Acids , Receptors, G-Protein-Coupled , Amino Acids/metabolism , Hormones , Lactates , Receptors, G-Protein-Coupled/metabolism , Succinates
10.
Cancer Res ; 82(7): 1267-1282, 2022 04 01.
Article in English | MEDLINE | ID: mdl-35135811

ABSTRACT

Lactate is an abundant oncometabolite in the tumor environment. In prostate cancer, cancer-associated fibroblasts (CAF) are major contributors of secreted lactate, which can be taken up by cancer cells to sustain mitochondrial metabolism. However, how lactate impacts transcriptional regulation in tumors has yet to be fully elucidated. Here, we describe a mechanism by which CAF-secreted lactate is able to increase the expression of genes involved in lipid metabolism in prostate cancer cells. This regulation enhanced intracellular lipid accumulation in lipid droplets (LD) and provided acetyl moieties for histone acetylation, establishing a regulatory loop between metabolites and epigenetic modification. Inhibition of this loop by targeting the bromodomain and extraterminal protein family of histone acetylation readers suppressed the expression of perilipin 2 (PLIN2), a crucial component of LDs, disrupting lactate-dependent lipid metabolic rewiring. Inhibition of this CAF-induced metabolic-epigenetic regulatory loop in vivo reduced growth and metastasis of prostate cancer cells, demonstrating its translational relevance as a therapeutic target in prostate cancer. Clinically, PLIN2 expression was elevated in tumors with a higher Gleason grade and in castration-resistant prostate cancer compared with primary prostate cancer. Overall, these findings show that lactate has both a metabolic and an epigenetic role in promoting prostate cancer progression. SIGNIFICANCE: This work shows that stromal-derived lactate induces accumulation of lipid droplets, stimulates epigenetic rewiring, and fosters metastatic potential in prostate cancer.


Subject(s)
Lipid Metabolism , Prostatic Neoplasms , Epigenesis, Genetic , Humans , Lactic Acid/metabolism , Lipid Metabolism/genetics , Male , Prostate/pathology , Prostatic Neoplasms/pathology
11.
Trends Endocrinol Metab ; 33(4): 231-235, 2022 04.
Article in English | MEDLINE | ID: mdl-35168874

ABSTRACT

The tumor ecosystem evolves with dynamic interactions between cancer and normal cells, and nutrients have emerged as new regulators of cancer hallmarks. Lactate has climbed the rankings as a multifunctional molecule orchestrating many aspects of the disease onset and progression. Here, we patchwork and discuss the main recent findings conferred during the EMBO workshop titled 'Lactate: Unconventional Roles of a Nutrient Along the Tumor Landscape.'


Subject(s)
Lactic Acid , Neoplasms , Ecosystem , Humans
13.
Front Oncol ; 10: 396, 2020.
Article in English | MEDLINE | ID: mdl-32266157

ABSTRACT

Neoplastic tissues are composed not only by tumor cells but also by several non-transformed stromal cells, such as cancer-associated fibroblasts, endothelial and immune cells, that actively participate to tumor progression. Starting from the very beginning of carcinogenesis, tumor cells, through the release of paracrine soluble factors and vesicles, i.e., exosomes, modify the behavior of the neighboring cells, so that they can give efficient support for cancer cell proliferation and spreading. A mandatory role in tumor progression has been recently acknowledged to metabolic deregulation. Beside undergoing a metabolic reprogramming coherent to their high proliferation rate, tumor cells also rewire the metabolic assets of their stromal cells, educating them to serve as nutrient donors. Hence, an alteration in the composition and in the flow rate of many nutrients within tumor microenvironment has been associated with malignancy progression. This review is focused on metabolic remodeling of the different cell populations within tumor microenvironment, dealing with reciprocal re-education through the symbiotic sharing of metabolites, behaving both as nutrients and as transcriptional regulators, describing their impact on tumor growth and metastasis.

14.
Br J Cancer ; 122(9): 1354-1366, 2020 04.
Article in English | MEDLINE | ID: mdl-32132656

ABSTRACT

BACKGROUND: Metabolic reprogramming towards aerobic glycolysis in cancer supports unrestricted cell proliferation, survival and chemoresistance. The molecular bases of these processes are still undefined. Recent reports suggest crucial roles for microRNAs. Here, we provide new evidence of the implication of miR-27a in modulating colorectal cancer (CRC) metabolism and chemoresistance. METHODS: A survey of miR-27a expression profile in TCGA-COAD dataset revealed that miR-27a-overexpressing CRCs are enriched in gene signatures of mitochondrial dysfunction, deregulated oxidative phosphorylation, mTOR activation and reduced chemosensitivity. The same pathways were analysed in cell lines in which we modified miR-27a levels. The response to chemotherapy was investigated in an independent cohort and cell lines. RESULTS: miR-27a upregulation in vitro associated with impaired oxidative phosphorylation, overall mitochondrial activities and slight influence on glycolysis. miR-27a hampered AMPK, enhanced mTOR signalling and acted in concert with oncogenes and tumour cell metabolic regulators to force an aerobic glycolytic metabolism supporting biomass production, unrestricted growth and chemoresistance. This latter association was confirmed in our cohort of patients and cell lines. CONCLUSIONS: We disclose an unprecedented role for miR-27a as a master regulator of cancer metabolism reprogramming that impinges on CRC response to chemotherapy, underscoring its theragnostic properties.


Subject(s)
Colorectal Neoplasms/drug therapy , MicroRNAs/genetics , Protein Kinases/genetics , TOR Serine-Threonine Kinases/genetics , AMP-Activated Protein Kinase Kinases , Adult , Aged , Aged, 80 and over , Cell Proliferation/drug effects , Cellular Reprogramming/drug effects , Cellular Reprogramming/genetics , Cisplatin/pharmacology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/radiotherapy , Drug Resistance, Neoplasm/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , HCT116 Cells , Humans , Male , Middle Aged , Signal Transduction/drug effects
15.
Front Oncol ; 10: 256, 2020.
Article in English | MEDLINE | ID: mdl-32185131

ABSTRACT

Mitochondria play multifaceted roles in malignant tumor progression. Beyond their bioenergetic role, mitochondria are essential for providing malignant cells a higher plasticity to face the harsh environmental conditions. Cell-autonomous metabolic deregulation of cancer cells, or metabolic adaptation to microenvironmental cues (lack of nutrients, stromal supply, hypoxia, etc.), represent the triggering event of mitochondria overexploitation to orchestrate nutrient sensing and upload, signaling, and redox circuits. As readout of their higher function, mitochondria produce high amounts of reactive oxygen species (ROS) that are functional for multiple signaling networks underlying tumor proliferation, survival, and metastatic process. To compensate for the higher rate of mitochondrial ROS production, cancer cells have evolved adaptive mechanisms to increase their antioxidant systems and to address ROS activating pathways useful for the tumor cell adaptation to environmental changes. As these properties are critical for cancer progression, mitochondrial ROS have recently become an attractive target for anti-cancer therapies. We discuss how understanding of mitochondrial function in the tumor-specific generation of ROS will impact on the development of novel redox-based targeted therapeutic strategies.

16.
Cells ; 9(3)2020 03 10.
Article in English | MEDLINE | ID: mdl-32164162

ABSTRACT

The majority of breast cancers express the estrogen receptor (ER) and are dependent on estrogen for their growth and survival. Endocrine therapy (ET) is the standard of care for these tumors. However, a superior outcome is achieved in a subset of ER positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer patients when ET is administrated in combination with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, such as palbociclib. Moreover, CDK4/6 inhibitors are currently being tested in ER+/HER2+ breast cancer and reported encouraging results. Despite the clinical advances of a combinatorial therapy using ET plus CDK4/6 inhibitors, potential limitations (i.e., resistance) could emerge and the metabolic adaptations underlying such resistance warrant further elucidation. Here we investigate the glucose-dependent catabolism in a series of isogenic ER+ breast cancer cell lines sensitive to palbociclib and in their derivatives with acquired resistance to the drug. Importantly, ER+/HER2- and ER+/HER2+ cell lines show a different degree of glucose dependency. While ER+/HER2- breast cancer cells are characterized by enhanced aerobic glycolysis at the time of palbociclib sensitivity, ER+/HER2+ cells enhance their glycolytic catabolism at resistance. This metabolic phenotype was shown to have prognostic value and was targeted with multiple approaches offering a series of potential scenarios that could be of clinical relevance.


Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Glucose/metabolism , Piperazines/therapeutic use , Pyridines/therapeutic use , Antineoplastic Agents/pharmacology , Breast Neoplasms/genetics , Cell Line, Tumor , Female , Humans , Piperazines/pharmacology , Pyridines/pharmacology , Transfection
18.
Semin Cell Dev Biol ; 98: 71-79, 2020 02.
Article in English | MEDLINE | ID: mdl-31108187

ABSTRACT

Metabolic reprogramming as well as the flexible utilisation of fuel sources by tumour cells has been considered not only intrinsic to malignant cells but also sustained by resident and/or recruited stromal cells. The complexity of tumour-stroma cross-talk is experienced by neoplastic cells through profound changes in the own metabolic machinery. In such context, mitochondria are dynamic organelles that receive, orchestrate and exchange a multiplicity of stromal cues within the tumour cells to finely regulate key metabolic and signalling pathways, allowing malignant cells to adapt and thrive in an ever-changing environment. In this review, we focus on how tumour mitochondria are coached by stromal metabolic supply and how this re-education sustains tumour malignant traits.


Subject(s)
Epithelial-Mesenchymal Transition , Mitochondria/metabolism , Neoplasms/metabolism , Stromal Cells/metabolism , Humans , Neoplasms/pathology
19.
Cell Rep ; 28(1): 104-118.e8, 2019 07 02.
Article in English | MEDLINE | ID: mdl-31269432

ABSTRACT

Endocrine therapy (ET) is the standard of care for estrogen receptor-positive (ER+) breast cancers. Despite its efficacy, ∼40% of women relapse with ET-resistant (ETR) disease. A global transcription analysis in ETR cells reveals a downregulation of the neutral and basic amino acid transporter SLC6A14 governed by enhanced miR-23b-3p expression, resulting in impaired amino acid metabolism. This altered amino acid metabolism in ETR cells is supported by the activation of autophagy and the enhanced import of acidic amino acids (aspartate and glutamate) mediated by the SLC1A2 transporter. The clinical significance of these findings is validated by multiple orthogonal approaches in a large cohort of ET-treated patients, in patient-derived xenografts, and in in vivo experiments. Targeting these amino acid metabolic dependencies resensitizes ETR cells to therapy and impairs the aggressive features of ETR cells, offering predictive biomarkers and potential targetable pathways to be exploited to combat or delay ETR in ER+ breast cancers.


Subject(s)
Amino Acid Transport Systems/metabolism , Aspartic Acid/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Drug Resistance, Neoplasm/genetics , Excitatory Amino Acid Transporter 2/metabolism , Glutamic Acid/metabolism , Amino Acid Transport Systems/genetics , Amino Acid Transport Systems, Neutral/genetics , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Drug Resistance, Neoplasm/drug effects , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Excitatory Amino Acid Transporter 2/genetics , Female , GATA2 Transcription Factor/genetics , GATA2 Transcription Factor/metabolism , Gas Chromatography-Mass Spectrometry , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Humans , Mice , Mice, Inbred BALB C , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasm Metastasis , Prognosis , Transcriptome/genetics , Transplantation, Heterologous
20.
Oncogene ; 38(27): 5339-5355, 2019 07.
Article in English | MEDLINE | ID: mdl-30936458

ABSTRACT

Cancer-associated fibroblasts (CAFs) are the major cellular stromal component of many solid tumors. In prostate cancer (PCa), CAFs establish a metabolic symbiosis with PCa cells, contributing to cancer aggressiveness through lactate shuttle. In this study, we report that lactate uptake alters the NAD+/NADH ratio in the cancer cells, which culminates with SIRT1-dependent PGC-1α activation and subsequent enhancement of mitochondrial mass and activity. The high exploitation of mitochondria results in tricarboxylic acid cycle deregulation, accumulation of oncometabolites and in the altered expression of mitochondrial complexes, responsible for superoxide generation. Additionally, cancer cells hijack CAF-derived functional mitochondria through the formation of cellular bridges, a phenomenon that we observed in both in vitro and in vivo PCa models. Our work reveals a crucial function of tumor mitochondria as the energy sensors and transducers of CAF-dependent metabolic reprogramming and underscores the reliance of PCa cells on CAF catabolic activity and mitochondria trading.


Subject(s)
Mitochondria/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Cell Line, Tumor , Citric Acid Cycle , Fibroblasts/pathology , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Male , NAD/metabolism , Neoplasm Invasiveness , Oxidative Phosphorylation , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Reactive Oxygen Species/metabolism , Sirtuin 1/metabolism
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