The cancer cell 'energy grid': TGF-β1 signaling coordinates metabolism for migration.
Ontology highlight
ABSTRACT:
SUBMITTER: Jiang L
PROVIDER: S-EPMC4905294 | biostudies-other | 2015 Jul-Sep
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Idiopathic pulmonary fibrosis (IPF) is a serious lung disease characterized by excessive collagen matrix deposition and extracellular remodeling. Signaling pathways mediated by fibrotic cytokine transforming growth factor β1 (TGF-β1) make important contributions to pulmonary fibrosis, but it remains unclear how TGF-β1 alters metabolism and modulates the activation and differentiation of pulmonary fibroblasts. We found that TGF-β1 lowers NADH and NADH/NAD levels, possibly due to changes in the TCA cycle, resulting in reductions in the ATP level and oxidative phosphorylation in pulmonary fibroblasts. In addition, we showed that butyrate (C4), a short chain fatty acid (SCFA), exhibits potent antifibrotic activity by inhibiting expression of fibrosis markers. Butyrate treatment inhibited mitochondrial elongation in TGF-β1-treated lung fibroblasts and increased the mitochondrial membrane potential (MMP). Consistent with the mitochondrial observations, butyrate significantly increased ADP, ATP, NADH, and NADH/NAD levels in TGF-β1-treated pulmonary fibroblasts. Collectively, our findings indicate that TGF-β1 induces changes in mitochondrial dynamics and energy metabolism during myofibroblast differentiation, and that these changes can be modulated by butyrate, which enhances mitochondrial function.
| S-EPMC8143476 | biostudies-literature
Project description:TGF-β signaling plays a pivotal role in promoting tumor cell migration and cancer metastasis. ΔNp63α and TAp63α are two major isoforms of p53-related p63 protein. Our recent study has shown that TGF-β1 promotes ΔNp63α protein degradation to facilitate cancer metastasis. However, whether TAp63α is involved in TGF-β1-induced cancer metastasis remains unclear. In this study, we show that, in human pancreatic cancer MIA PaCa-2 cells harboring p53-R248W allele, TGF-β1 can significantly inhibit TAp63α protein stability in a Smad pathway-independent manner. Lysosome inhibitor, chloroquine, but not proteasome inhibitor MG132, can rescue TGF-β1-induced downregulation of TAp63α protein. In addition, we show that either TGF-β1 treatment or silencing of TAp63α can dramatically increase migration of MIA PaCa-2 cells. Importantly, the restored expression of TAp63α can effectively block TGF-β1-induced migration of MIA PaCa-2 cells. Mechanistically, we show that TGF-β1 promotes TAp63α protein degradation, leading to upregulation of p53-R248W protein expression, and consequently resulting in elevated MIA PaCa-2 cell migration. Together, this study indicates that lysosomal degradation is an important way for regulating TAp63α protein fate and highlights that TGF-β1-TAp63α-mutant p53 axis is critically important in pancreatic cancer metastasis.
| S-EPMC8301043 | biostudies-literature
Project description:Sigma-1 receptor (S1R) is an important endoplasmic reticulum chaperone with various functions in health and disease. The purpose of the current work was to elucidate the involvement of S1R in cancer energy metabolism under its basal, activated, and inactivated states. For this, two cancer cell lines that differentially express S1R were treated with S1R agonist, (+)-SKF10047, and antagonist, BD1047. The effects of the agonist and antagonist on cancer energy metabolism were studied using single-cell fluorescence microscopy analysis of real-time ion and metabolite fluxes. Our experiments revealed that S1R activation by agonist increases mitochondrial bioenergetics of cancer cells while decreasing their reliance on aerobic glycolysis. S1R antagonist did not have a major impact on mitochondrial bioenergetics of tested cell lines but increased aerobic glycolysis of S1R expressing cancer cell line. Our findings suggest that S1R plays an important role in cancer energy metabolism and that S1R ligands can serve as tools to modulate it.
| S-EPMC9221035 | biostudies-literature
Project description:Tumor-associated neutrophils are found in many types of cancer and are often reported to contribute to negative outcomes. The presence of transforming growth factor-beta (TGF-β) in the tumor microenvironment reportedly contributes to the skewing of neutrophils to a more pro-tumor phenotype. The effects of TGF-β on neutrophil signaling and migration are, however, unclear. We sought to characterize TGF-β signaling in both primary human neutrophils and the neutrophil-like cell line HL-60 and determine whether it directly induces neutrophil migration. We found that TGF-β1 does not induce neutrophil chemotaxis in transwell or underagarose migration assays. TGF-β1 does activate canonical signaling through SMAD3 and noncanonical signaling through ERK1/2 in neutrophils in a time- and dose-dependent manner. Additionally, TGF-β1 present in the tumor-conditioned media (TCM) of invasive breast cancer cells results in SMAD3 activation. We discovered that TCM induces neutrophils to secrete leukotriene B4 (LTB4), which is a lipid mediator important for amplifying the range of neutrophil recruitment. However, TGF-β1 alone does not induce secretion of LTB4. RNA-sequencing revealed that TGF-β1 and TCM alter gene expression in HL-60 cells, including the mRNA levels of the pro-tumor oncostatin M (OSM) and vascular endothelial growth factor A (VEGFA). These new insights into the role and impact of TGF-β1 on neutrophil signaling, migration, and gene expression have significant implications in the understanding of the changes in neutrophils that occur in the tumor microenvironment.
| S-EPMC10490904 | biostudies-literature
Project description:Tumor-associated neutrophils are found in many types of cancer and are often reported to contribute to negative outcomes. Several studies have shown that the presence of TGF-β in the tumor microenvironment contributes to the skewing of neutrophils to have a more pro-tumor phenotype. However, the direct effects of TGF-β on neutrophil signaling and migration are unclear. We sought to characterize TGF-β signaling in both primary human neutrophils and the neutrophil-like cell line HL-60 and determine whether TGF-β directly induces neutrophil migration. We found that TGF-β1 does not induce neutrophil migration in either a transwell or an underagarose migration assay. However, TGF-β1 does activate signals canonically through SMAD3 and noncanonically through ERK1/2 in neutrophils in a time and dose-dependent manner. Additionally, TGF-β1 present in the tumor-conditioned media (TCM) is responsible for SMAD3 activation. Moreover, we discovered that TCM from aggressive breast cancer cells induces neutrophils to secrete leukotriene B4 (LTB4), which is a lipid mediator important for amplifying neutrophil recruitment. However, we found that TGF-β1 alone does not induce secretion of LTB4. We next performed RNA-sequencing to evaluate the effects of TGF-β1 and TCM on the neutrophil transcriptome. We found that TGF-β1 and TCM result in changes in gene transcription in HL-60 cells, specifically of two pro-tumor genes OSM and VEGFA. Together, our findings characterize the effects of TGF-β1 on neutrophil signaling, migration, and gene expression that can be applied to understanding the changes in neutrophils that occur in the tumor microenvironment.
2023-08-10 | GSE230490 | GEO
Project description:Prolonged and elevated transforming growth factor-β1 (TGF-β1) signaling can lead to undesired scar formation during tissue repair and fibrosis that is often a result of chronic inflammation in the lung, kidney, liver, heart, skin, and joints. We report new TGF-β1 binding peptides that interfere with TGF-β1 binding to its cognate receptors and thus attenuate its biological activity. We identified TGF-β1 binding peptides from the TGF-β1 binding domains of TGF-β receptors and engineered their sequences to facilitate chemical conjugation to biomaterials using molecular docking simulations. The in vitro binding studies and cell-based assays showed that RIPΔ, which was derived from TGF-β type I receptor, bound TGF-β1 in a sequence-specific manner and reduced the biological activity of TGF-β1 when the peptide was presented either in soluble form or conjugated to a commonly used synthetic biomaterial. This approach may have implications for clinical applications such as treatment of various fibrotic diseases and soft tissue repair and offer a design strategy for peptide antibodies based on the biomimicry of ligand-receptor interactions.
| S-EPMC9254699 | biostudies-literature
Project description:HoxB9, as a HOX family member, is known to play important roles in embryonic development. Recent studies have shown that HoxB9 is involved in cancer progression. However, little is known about the role of HoxB9 and the underlying mechanisms that suppress oral squamous cell carcinoma (OSCC) progression. In the present study, we used immunohistochemical staining to demonstrate that HoxB9 is over-expressed in OSCC cells and found that high levels of HoxB9 were significantly associated with shorter overall survival in patients with OSCC. Functional studies revealed that knocking down HoxB9 in OSCC cells using RNA interference decreased the migration and invasion of OSCC cells in vitro. Our mechanistic studies suggested that HoxB9 could stimulate the migration and invasion of OSCC cells by targeting EMT via the TGF-β1/Smad2/Slug signaling pathway. Collectively, these findings suggest the vital roles of HoxB9 in OSCC progression through its effects in promoting EMT.
| S-EPMC5376006 | biostudies-literature
Project description:In this study, we analyzed GPC family genes in colorectal cancer (CRC) and the possible mechanism of action of GPC1 in CRC. CRC patient data were extracted from The Cancer Genome Atlas, and the prognostic significance of GPC1 expression and its association with clinicopathological features were identified by Kolmogorov-Smirnov test. CRC patients with high GPC1 expression had poor overall survival compared with patients with low GPC1 expression. In vitro experiments demonstrated that knockdown of GPC1 significantly inhibited the proliferation and migration and promoted cell apoptosis in CRC cell lines. Gene Ontology analysis of differential genes indicated that GPC1 may influence the TGF-β1 signaling pathway. Additional experiments revealed that silencing GPC1 suppressed the levels of TGF-β1 and p-SMAD2 but increased the expression of SMAD2. Taken together, these findings suggest that GPC1 may function as a tumor promoter in CRC cells through promoting TGF-β signaling pathway. Our results also indicate that GPC1 may serve as a critical effector in CRC progression and a new potential target for CRC therapy.
| S-EPMC9173621 | biostudies-literature
Project description:A widespread degenerative condition of the aorta, abdominal aortic aneurysm (AAA), severely endangers the health of middle-aged and elderly people. SPARC related modular calcium binding2 (SMOC2) is upregulated in the carotid arteries of rats with atherosclerotic lesions, but its function in AAA is still unknown. Therefore, the aim of this research was to evaluate the function of SMOC2 in AAA. The results showed that in the AAA tissues, SMOC2 expression was upregulated compared with healthy controls. Overexpression of SMOC2 promoted vascular smooth muscle cells (VSMCs) proliferation, migration, and extracellular matrix (ECM) degradation. In contrast, silence of SMOC2 inhibited VSMCs proliferation, migration, and ECM degradation. Overexpression of SMOC2 promoted BMP and TGF-β1 expression and silence of SMOC2 had an opposite effect. Besides, inhibition of BMP or TGF-β1 suppressed VSMCs cell proliferation, migration, and ECM degradation. Moreover, inhibition BMP or TGF-β1 reversed the promotive effects of SMOC2 overexpression on VSMCs proliferation, migration, and ECM degradation. SMOC2 may affecte the formation of AAA by upregulating BMP and TGF-β1 to regulate the proliferation, migration, and ECM degradation of VSMCs.
| S-EPMC10493216 | biostudies-literature
Project description:Bone regeneration following injury is initiated by inflammatory signals and occurs in association with infiltration by sensory nerve fibers. Together, these events are believed to coordinate angiogenesis and tissue reprogramming, but the mechanism of coupling immune signals to reinnervation and osteogenesis is unknown. Here, we found that nerve growth factor (NGF) is expressed following cranial bone injury and signals via p75 in resident mesenchymal osteogenic precursors to affect their migration into the damaged tissue. Mice lacking Ngf in myeloid cells demonstrated reduced migration of osteogenic precursors to the injury site with consequently delayed bone healing. These features were phenocopied by mice lacking p75 in Pdgfra+ osteoblast precursors. Single-cell transcriptomics identified mesenchymal subpopulations with potential roles in cell migration and immune response, altered in the context of p75 deletion. Together, these results identify the role of p75 signaling pathway in coordinating skeletal cell migration during early bone repair.
| S-EPMC8932666 | biostudies-literature