Oxidative phosphorylation inhibition with IACS-010759 treatment in colorectal cancer cells
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PROVIDER: PRJNA1022401 | ENA |
REPOSITORIES: ENA
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Project description:Although targeting oxidative phosphorylation (OXPHOS) in cancer is currently impeded due to dose-limiting toxicities, there remain opportunities through combination treatments that provide therapeutic benefits at doses attainable in patients. While glycolysis-deficient cancers are generally vulnerable to OXPHOS inhibition in preclinical models, the full extent of phenotypical and mechanistic consequences of inhibiting OXPHOS in cancers capable of glycolysis is not yet well understood. We aimed to clarify the response and underlying mechanisms of glycolysis-competent colorectal cancer (CRC) to OXPHOS inhibition and to identify potential approaches to render such cells more sensitive to OXPHOS inhibitors.
2025-01-13 | GSE244319 | GEO
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Project description:Protein phosphatase 2A (PP2A) is a promiscuous enzyme affecting cellular physiology. It is unclear however, which of the cellular processes are most perturbed upon PP2A inhibition and how such perturbations could be exploited therapeutically. Here, we report an unanticipated sensitivity of the splicing machinery to phosphorylation changes in response to PP2A inhibition by LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. Changed phosphorylation endows LB-100 treated colorectal adenocarcinoma cells with differential splicing patterns. Over 1000 exon skipping and intron retention events in PP2A-inhibited cells affect predominantly regulators of genomic integrity. Finally, LB-100-evoked alternative splicing is predicted to be a source of neoantigens that can improve cancer treatment responses to immune modulators. Our findings provide a potential explanation for the pre-clinical and clinical observations that PP2A inhibition sensitizes cancer cells to immune checkpoint blockade and genotoxic agents.
2024-04-11 | GSE236625 | GEO
Project description:The Warburg effect, consisting of increased glucose uptake and glycolysis, provides metabolic energy as well as cellular building blocks for tumor growth. Inhibition of the Warburg effect with 2-deoxyglucose (2DG) has been explored in clinical trials with limited efficacy. Blockage of glycolysis can induce autopahgy resulting in alternative energy generation through oxidative phosphorylation providing a potential bypass of the effects of inhibition of glycolysis. Here in we demonstrate that activation of AMPK, as a consequence of energetic stress, induces mitochondrial energy production potentially bypassing the effects of glycolysis inhibition. We thus combined blockage of glycolysis by 2DG with inhibition of the electron transfer complex I (ETC1) in the mitochondria with the clinically applicable antidiabetic drug metformin. The combination resulted in activation of AMPK and autopahgy that however rendered eventual depletion of ATP and cell death. Furthermore, combined inhibition of glycolysis and mitochondrial respiration inhibited tumor growth and markedly decreased metastatic capacity in vivo. In order to understand the mechanism of these metabolic inhibitors, we performed whole genome transcriptional analysis. Human SK-4 esophageal cancer cell lines were treated with 5 different treatment groups [2 deoxy glucose (4mM), Metformin (5mM), AICAR (2mM), 2 deoxy glucose (4mM) plus Metformin (5mM) and 2 deoxy glucose (4mM) plus AICAR (2mM)] with non treated control groups for 12 hrs. Each groups was quadruplicated. Microarray experiments and data analysis were done at Dept. of Systems Biology, MDACC (Houston, USA)
2012-12-31 | E-GEOD-16816 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Nearly 50% of the patients who receive the most intensive treatment develop leukemia relapse. AML cells are highly dependent on mitochondrial oxidative phosphorylation (OXPHOS) for survival, especially refractory leukemia, but how OXPHOS contributes to the leukemia progression is unclear and noncytotoxic strategy to inhibit OXPHOS is lacking. Here, we demonstrate for the first time that ZDHHC21 palmitoyltransferase serves as a key regulator to regulate the OXPHOS hyperactivity in AML cells. The depletion of ZDHHC21 effectively inhibited OXPHOS activity and induced the myeloid differentiation of AML cell lines and patient-derived AML specimens. Mechanistically, ZDHHC21 specifically catalyzes the palmitoylation of mitochondrial kinase AK2 and further activates OXPHOS to arrest myeloid differentiation. Moreover, inhibition of ZDHHC21 eradicated the AML blasts and prolonged the survival of NOD/SCID mice inoculated with AML cell lines and PDX-AML cells. Besides, targeting ZDHHC21 to suppress OXPHOS markedly enhances the chemotherapy efficacy in refractory leukemia. Together, these findings not only uncover the new biological function of palmitoyltransferase ZDHHC21 in regulating AML oxidative phosphorylation, but also indicate ZDHHC21 inhibition as a potential therapy for patients with AML especially refractory leukemia.
2024-11-30 | GSE218229 | GEO
Project description:Peritoneal metastases (PM) in colorectal cancer (CRC) present a significant challenge due to limited treatment options and poor patient prognosis. While cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) offers curative potential for selected patients, its overall benefit remains limited compared to surgery alone. In this study we show that the majority of CRC-PM represent the CMS4-subtype. Despite CRS-HIPEC treatment, CMS4 patients had high rates of recurrent disease and mortality, indicating limited effectiveness of the treatment. To explore alternative treatment approaches, we queried large-scale compound screens and discovered the copper (Cu)-ionophore elesclomol (ES) as a highly effective agent against CMS4-specific disease models. ES exhibited rapid and selective cytotoxicity against CMS4 cells by targeting the oxidative phosphorylation machinery. CMS4 cells had reduced absolute mitochondrial content and lower expression of genes involved in oxidative phosphorylation, making them vulnerable to ES-induced cytotoxicity. Short exposures to ES combined with Cu (ES-Cu) resulted in near-complete growth inhibition of cancer cells, suggesting its potential for HIPEC-like intra-abdominal treatment procedures. Furthermore, ES-Cu demonstrated efficacy in preclinical models of PM, including CRC-PM and ovarian cancer organoids, and a HIPEC rat model of PM. These findings highlight ES-Cu as promising candidate for the local treatment of CRC-PM, with broader implications for other cancer types characterized by high incidence of PM.
2024-05-01 | GSE242676 | GEO
Project description:The cellular stress response triggers a cascade of events leading to transcriptional reprogramming and a transient inhibition of global protein synthesis, which is thought to be mediated by phosphorylation of eukaryotic initiation factor-2α (eIF2α). Using mouse embryonic fibroblasts (MEFs) and the fission yeast S. pombe, we report that rapid translational arrest and cell survival in response to hydrogen peroxide-induced oxidative stress do not rely on eIF2a kinases and eIF2a phosphorylation. Rather H2O2 induces a block in elongation through phosphorylation of eukaryotic elongation factor 2 (eEF2). Kinetic and dose-response analyses uncovered crosstalk between the eIF2a and eEF2 phosphorylation pathways, indicating that, in MEFs, eEF2 phosphorylation initiates the acute shutdown in translation, which is maintained by eIF2a phosphorylation. Our results challenge the common conception that eIF2a phosphorylation is the primary trigger of translational arrest in response to oxidative stress and point to integrated control that may facilitate the survival of cancer cells.
2019-09-14 | GSE137409 | GEO
Project description:Transcriptional regulation of Th17 differentiation by mitochondrial oxidative phosphorylation
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Project description:Poly(ADP-ribose) Polymerase 1 (PARP-1) is a nuclear enzyme that catalyse the transfer of ADP-ribose units from NAD+ to several target proteins involved in cellular stress responses. Using the cell line WRL68, we have previously shown that the activation of PARP-1 induced by oxidative stress after H2O2 treatment lead to depletion of cellular NAD+ and ATP, which promote cell death. In this work, we used LC-MS/MS based phosphoproteomics to show that the oxidative damage induced by H2O2 treatment modified the phosphorylation of several proteins in WRL68 cells, most of them related to transcription process. Interestingly, genetic or pharmacological inhibition of PARP-1 reduced the phosphorylation of YAP1, a transcriptional coactivator involved in cell survival, in WRL68 cells after H2O2 treatment. Inhibition of PARP-1 increased cell viability after oxidative treatment and diminished the degradation of YAP1; the elimination of YAP1 by gene silencing abrogated the protective effect of PARP-1 inhibition, indicating that YAP1 is important for the survival of WRL68 cells after oxidative damage. In the same way, the supplementation of NAD+, substrate of PARP-1, on WRL68 cells suffering oxidative damage reduced the phosphorylation of YAP1, suggesting that the loss of cellular NAD+ caused by PARP-1 activation after oxidative treatment is responsible for the phosphorylation of YAP1. Finally, PARP-1 silencing after oxidative treatment diminished the activation of AMPK, a master regulator of cell metabolism implicated in the restoration of energy balance during metabolic stress. Since NAD+ supplementation reduced the phosphorylation of some AMPK substrates in WRL68 cells after oxidative treatment, we hypothesize that the loss of cellular NAD+ after PARP-1 activation may induce a metabolic stress that activates AMPK. In summary, we showed a new crucial role of PARP-1 in the response to oxidative stress in WRL68 cells; PARP-1 activation reduces the cell viability by promoting the phosphorylation and degradation of YAP1, which is mediated by the energy stress caused by PARP-1 activation.
2020-12-18 | PXD019823 | Pride