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Post-translational regulation of metabolism in Fumarate Hydratase deficient cancer cells

ABSTRACT: This data-set contains proteomics and phosphoproteomics of human FH-deficient UOK262 cells and their FH-complemented counterpart.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

SUBMITTER: Vinothini Rajeeve

LAB HEAD: Vinothini Rajeeve

PROVIDER: PXD006693 | Pride | 2017-11-28

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	F001314.mzid	Mzid
	F001315.mzid	Mzid
	F001316.mzid	Mzid
	F001317.mzid	Mzid
	F001318.mzid	Mzid

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1 - 5 of 36

Publications

Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells.

Gonçalves Emanuel E Sciacovelli Marco M Costa Ana S H ASH Tran Maxine Gia Binh MGB Johnson Timothy Isaac TI Machado Daniel D Frezza Christian C Saez-Rodriguez Julio J

Metabolic engineering 20171127

Deregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in fumarate hydratase (FH) deficient cells and developed a computational modelling approach to identify putat ...[more]

PMID: 29191787

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ECM-enriched proteomics of human fallopian tube, fimbria and ovarian tissue

Project description:We analysed the extracellular matrix (ECM) landscape of fresh, healthy tissues from human fallopian tube (FT), fimbria (FB, the tissue of origin of serous tubal intraepithelial lesions) and ovarian tissue (OV). The aim was to identify differentially expressed matrix proteins between FB and FT or OV which may promote the neoplastic transformation of serous tubal intraepithelial lesions (STICs) into high-grade serous ovarian cancer, HGSOC, and metastasis from the FB to the OV.

2022-06-20 | PXD023912 | Pride

Balance between B55alpha and Greatwall expression levels predicts sensitivity to Greatwall inhibition in cancer cells

Project description:The Greatwall kinase is a key cell cycle regulator responsible for the timely inactivation of PP2A-B55 phosphatases and consequential stabilisation of critical Cdk1-driven mitotic phosphorylation. Although Greatwall represents a potential oncogene and prospective therapeutic target, our understanding of cellular and molecular responses to chemical Greatwall inactivation remains limited. To address this, we introduce C-604, a highly selective Greatwall inhibitor, and characterise both immediate and long-term cellular responses to the chemical attenuation of Greatwall activity. We provide evidence suggesting that ENSA(S67), ARPP19(S62) and the Greatwall autophosphorylation site (T878) represent the only mitotic Greatwall substrates. Additionally, we demonstrate that Greatwall inhibition causes systemic destabilisation of mitotic phosphoproteome, premature mitotic exit and pleiotropic cellular pathologies. Importantly, we establish that cellular and molecular defects associated with low Greatwall activity arise from the untimely activation of PP2A complexes incorporating B55α but no other B55 isoforms, highlighting the unique role of PP2A-B55α phosphatases in shaping cellular responses to Greatwall-targeting compounds. Additionally, we show that sensitivity to Greatwall inhibition varies in different cell line models and that dependency on Greatwall activity reflects the balance between Greatwall and B55α expression levels. Our findings highlight Greatwall dependency as a cell-specific vulnerability and propose Greatwall and B55α expression levels as predictive biomarkers of cellular responses to Greatwall-targeted therapeutics.

2025-07-21 | PXD059047 | Pride

Effect of the Src inhibitor peptide TAT-Cx43266-283 in lung cancer brain metastasis models.

Project description:Background: TAT-Cx43266-283 is a novel inhibitor of Src, which has shown important antitumor effects in preclinical models of glioblastoma. Because Src plays a pivotal role in several tumors, including lung cancer and brain metastasis, in this study we investigated the effect of TAT-Cx43266-283 in lung cancer brain metastasis, an unmet clinical need. Methods: Cancer Stem Cells (CSCs) from the murine lung cancer cell line LLC, named LLC-CSCs, were isolated and used to study the effect of TAT-Cx43266-283 in vitro and to develop an in vivo model of lung cancer brain metastasis. Thus, in vivo models were carried out performing an intracranial implantation of LLC-CSCs in immunocompetent mice and the impact of TAT-Cx43266-283 in these models was assessed. A phosphoproteomic analysis was employed to identify signaling pathways affected by TAT-Cx43266-283, and the most prominent targets were validated by immunofluorescence or Western Blot. Results: We found that TAT-Cx43266-283 significantly reduced LLC-CSCs viability and increased the survival of immunocompetent mice bearing lung cancer derived-brain metastatic tumors. Phosphoproteomic analysis identified ERK as a key effector of TAT-Cx43266-283 treatment in the LLC-CSC-derived brain metastasis model. TAT-Cx43266-283 also induced apoptosis of tumoral cells and disrupted the cytoskeleton and vascularization of the tumor tissue in this preclinical lung cancer brain metastasis model. Conclusions: Our results suggest that TAT-Cx43266-283 is a promising antitumoral drug for lung cancer brain metastasis treatment. We identified the inhibition of ERK as an important effector, together with the inhibition of Src, in the antitumoral effect of TAT-Cx43266-283 in lung cancer brain metastasis. All this together, places TAT-Cx43266-283 one step forward into its journey to its therapeutic implementation.

2026-03-02 | PXD058276 | Pride

Maternal Immune Activation imprints translational dysregulation and differential MAP2 phosphorylation in descendant neural stem cells

Project description:To undertake a comprehensive examination of the molecular mechanisms governing the alterations induced by maternal immune activation (MIA) during gestation that impacts the subsequent neurodevelopment of progeny, we have devised an in vitro model based on neural stem cells (NSCs) sourced from fetuses carried by animals subjected to Poly I:C treatment. These neural progenitors demonstrate proliferative properties and can be effectively differentiated into both neurons and glial cells. Through transcriptomic, proteomic, and phosphoproteomic analyses conducted on these cellular models, in conjunction with counterparts from control treatments, discernible shifts in the expression levels of a specific subset of proteins implicated in neuronal function were elucidated. Noteworthy is the absence of congruence between these alterations and the transcriptomic findings, suggesting a potential dysregulation at the level of protein translation. Furthermore, a discernible discrepancy in the basal phosphorylation of proteins was observed between differentiated cells from both experimental groups, particularly within proteins associated with cytoskeletal architecture and synaptic functionality, notably those belonging to the MAP family. These observed alterations were found to correlate with changes in neuronal function, particularly with respect to synaptic plasticity and the establishment of neuronal synapses, thereby reaffirming previous assertions regarding the potential impact of MAP2 function modulation via its phosphorylation state on neuronal structure and function.

2025-02-16 | PXD056291 | Pride

Fumarate hydratase orchestrates hepatic steatosis via ULK1 mediated lipophagy

Project description:Hepatic lipid homeostasis is coordinated by various metabolic pathways, such as lipogenesis, lipid uptake, storage, and oxidation. However, the underlying mechanism that orchestrates metabolic crosstalk remains unclarified. Herein, we demonstrated that fumarate hydratase (FH) functioned as an indispensable adaptor governing mitochondria metabolism and lipid droplets (LDs) degradation. Hepatic FH overexpression prevented hepatic steatosis in normal mice and ob/ob mice without interfering mitochondrial lipid oxidation and lipogenesis. Strikingly, we found that FH selectively activated lipophagy-mediated LDs lipidolysis. Mechanistically, FH interacted with ULK1 and stabilized ULK1 through preventing its ubiquitination and degradation, resulting in lipophagy activation and the elimination of hepatic lipid accumulation. Meanwhile, hepatic ULK1 deficiency abrogated the protective effects in FH-overexpressing mice. Also, we clarified that the interaction between FH and ULK1 occurred in cytoplasm, but not in mitochondria. Cytoplasmic FH was sensitive to lipids and downregulated without affecting mitochondrial FH in vivo. Moreover, the FH-ULK1 axis was identified closely associated with hepatic steatosis in human patients. Taken together, our research demonstrates a “two-side” insight of FH on hepatic lipid metabolism and provides a promising strategy for fatty liver treatment.

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Elucidating the role of the kinase activity of endothelial cell focal adhesion kinase in angiocrine signalling and tumour growth

Project description:A common limitation of cancer treatments is chemotherapy resistance. We have previously identified a molecular mechanism where chemotherapy resistance is regulated by endothelial cells. Endothelial cell specific knockout of focal adhesion kinase (FAK) sensitises tumour cells to DNA-damaging therapies, reducing tumour growth in mice. Our current study addresses the kinase dependent component of endothelial cell FAK sensitisation to the DNA damaging chemotherapeutic drug doxorubicin. FAK is recognised as a therapeutic target in tumour cells, leading to the development of a range of inhibitors, the majority being ATP competitive kinase inhibitors. We demonstrate that specific inactivation of the FAK kinase domain in endothelial cells of blood vessels in established subcutaneous B16F0 tumours sensitises melanoma cells to doxorubicin. Tumour growth was reduced in response to doxorubicin treatment in FAK kinase-dead but not in wild-type mice. Furthermore, we demonstrate that doxorubicin reduces perivascular proliferation, enhances apoptosis and DNA-damage in endothelial cell FAK kinase dead tumours. When we treated human pulmonary microvascular endothelial cells with the FAK kinase inhibitors defactinib, PF-562,271 and PF-573,228 in combination with doxorubicin, we observed a reduction in cytokine levels, implying a possible mechanism for FAK kinase domain in chemosensitisation. Together, these results confirm the role of the kinase domain of EC-FAK in chemosensitising tumour cells to doxorubicin.

2021-11-02 | PXD019728 | Pride

Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence

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2021-06-09 | PXD019186 | Pride

BRAF mutations disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mouse and humans

Project description:Germline mutations in BRAF and other components of the Mitogen-Activated Protein Kinase (MAPK) pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harboring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAFp.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression in cell cycle inhibitors, cell growth arrest and apoptosis but not tumour formation. Our findings show a critical role for BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans

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Characterising early phosphorylation events upon HER2 protein overexpression

Project description:HER2 transduced cells which we will refer to as HER2-DOX –. These cells are 99% GFP positive (i.e., 99% cells have HER2 transduced, un-induced). As a control, we had GFP empty vector transduced MCF10A cells (95% have GFP transduced). Both cell types in triplicates. We had 4 time-points 0h, 30 mins, 4hours, and 7 hours (time duration for which HER2 will be induced). DOX was added to the GFP-MCF10A cells as a control. Only 1ug/ml of DOX was be used.

2023-01-23 | PXD034105 | Pride

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