The regulators of peroxisomal acyl-carnitine shuttle CROT and CRAT promote metastasis in melanoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE208547 | GEO | 2022/08/25
REPOSITORIES: GEO
Similar Datasets
Project description:The regulators of peroxisomal acyl-carnitine shuttle CROT and CRAT promote metastasis in melanoma
| PRJNA860090 | ENA
Project description:The ability to survive following loss of adhesion underpins cancer metastasis and significantly contributes triple negative breast cancer (TNBC) morbidity. Epithelial cells that form solid tumors must evade anoikis, a special type of cell death that occurs upon detachment from the extracellular matrix in order to colonize in distal sites. While there have been several advances in the understanding of the mechanisms by which cells undergo anoikis, the role for noncoding RNAs (ncRNAs) in this process is less well understood. An important role for microRNAs (miRNAs) in regulating anoikis is beginning to emerge, however in general the mechanisms by which miRNAs regulate anoikis are largely unknown. Thus we utilized the anoikis-sensitive immortalized mammary epithelial cell line, MCF10A to unbiasedly determine the microRNAs differentially regulated upon detachment.
2023-10-30 | GSE244857 | GEO
Project description:Melanoma tumors are highly heterogeneous, comprising of many cell populations that vary in their potential for growth and invasion. Differential transcription factor expression contributes to these phenotypic traits. BRN2, a member of the POU domain family of transcription factors is thought to play important roles in melanoma invasion and metastasis. However, how BRN2 functions during the metastatic process of melanoma remains largely unknown. We therefore investigated the effects of BRN2 expression in melanoma cells with no or low constitutive expression using a doxycycline-inducible system. Induction of BRN2 expression led to reduced proliferation and partial resistance to an inhibitor of mutated BRAF. Whole genome profiling analysis revealed novel targets and signaling pathway changes related to prevention of cell death induced by detachment from the extracellular matrix, known as anoikis resistance. Further investigation confirmed increased survival of BRN2 expressing cell lines in non-adherent conditions. Functionally, expression of BRN2 promoted induction of c-MET levels as well as increased phosphorylation of STAT3. Treatment with crizotinib, a c-MET inhibitor, decreased cellular viability of BRN2 expressing cells under non-adherent conditions to death by anoikis. These results highlight the importance of a largely overlooked transcription factor in the progression and metastasis of melanoma, and may suggest a strategy to target BRN2 expressing cells resistant to therapy and cell death by anoikis.
2020-02-25 | GSE145806 | GEO
Project description:Peroxisomes carry out many essential lipid metabolic functions. Nearly all of these functions require that an acyl group-either a fatty acid or the acyl side chain of a steroid derivative-be thioesterified to coenzyme A (CoA) for subsequent reactions to proceed. This thioesterification, or "activation", reaction, catalyzed by enzymes belonging to the acyl-CoA synthetase family, is thus central to cellular lipid metabolism. However, despite our rather thorough understanding of peroxisomal metabolic pathways, surprisingly little is known about the specific peroxisomal acyl-CoA synthetases that participate in these pathways. Of the 26 acyl-CoA synthetases encoded by the human and mouse genomes, only a few have been reported to be peroxisomal, including ACSL4, SLC27A2, and SLC27A4. In this review, we briefly describe the primary peroxisomal lipid metabolic pathways in which fatty acyl-CoAs participate. Then, we examine the evidence for presence and functions of acyl-CoA synthetases in peroxisomes, much of which was obtained before the existence of multiple acyl-CoA synthetase isoenzymes was known. Finally, we discuss the role(s) of peroxisome-specific acyl-CoA synthetase isoforms in lipid metabolism.
| S-EPMC3382043 | biostudies-literature
Project description:Matrix-deprivation stress leads to cell-death by anoikis, whereas overcoming anoikis is critical for cancer metastasis. Work from our lab and others has identified a crucial role for the cellular energy sensor AMPK in anoikis-resistance, highlighting a key role for metabolic reprogramming in stress survival. Protein synthesis is a major energy-consuming process that is tightly regulated under stress. Although an increase in protein synthesis in AMPK-depleted experimentally-transformed MEFs has been associated with anoikis, the status and regulation of protein translation in epithelial-origin cancer cells facing matrix-detachment remains largely unknown. Our study shows that protein translation is mechanistically abrogated at both initiation and elongation stages by the activation of the unfolded protein response (UPR) pathway and inactivation of elongation factor eEF2, respectively. Additionally, we show inhibition of the mTORC1 pathway known for regulation of canonical protein synthesis. We further functionally assay this inhibition using SUnSET assay, which demonstrates repression of global protein synthesis in MDA-MB-231 and MCF7 breast cancer cells when subjected to matrix-deprivation. In order to gauge the translational status of matrix-deprived cancer cells, we undertook polysome profiling. Our data revealed reduced but continuous mRNA translation under matrix-deprivation stress. An integrated analysis of transcriptomic and proteomic data further identifies novel targets that may aid cellular adaptations to matrix-deprivation stress and can be explored for therapeutic intervention.
2023-06-14 | GSE234460 | GEO
Project description:To understand the contribution of adipose tissue fatty acid oxidation to whole-body metabolism, we generated mice with an adipose-specific knockout of carnitine palmitoyltransferase 2 (CPT2A?/?), an obligate step in mitochondrial long-chain fatty acid oxidation. CPT2A?/? mice became hypothermic after an acute cold challenge, and CPT2A?/? brown adipose tissue (BAT) failed to upregulate thermogenic genes in response to agonist-induced stimulation. The adipose-specific loss of CPT2 resulted in diet-dependent changes in adiposity but did not result in changes in body weight on low- or high-fat diets. Additionally, CPT2A?/? mice had suppressed high-fat diet-induced oxidative stress and inflammation in visceral white adipose tissue (WAT); however, high-fat diet-induced glucose intolerance was not improved. These data show that fatty acid oxidation is required for cold-induced thermogenesis in BAT and high-fat diet-induced oxidative stress and inflammation in WAT. http://www.sciencedirect.com/science/article/pii/S2211124714010523
2014-02-21 | ST000272 | MetabolomicsWorkbench
Project description:Gaining a deep understanding of the molecular mechanisms underlying ischemic stroke is necessary to develop treatment alternatives. Ischemic stroke is known to cause a cellular energy imbalance when glucose supply is deprived, enhancing the role for energy production via β-oxidation where acylcarnitines are essential for the transportation of fatty acids into the mitochondria. Although traditional bulk analysis methods enable sensitive detection of acylcarnitines, they do not provide information on their abundances in various tissue regions. However, with quantitative mass spectrometry imaging the detected concentrations and spatial distributions of endogenous molecules can be readily obtained in an unbiased way. Here, we use pneumatically assisted nanospray desorption electrospray ionization mass spectrometry imaging (PA nano-DESI MSI) doped with internal standards to study the distributions of acylcarnitines in mouse brain affected by stroke. The internal standards enable quantitative imaging and annotation of endogenous acylcarnitines is achieved by studying fragmentation patterns. We report a significant accumulation of long-chain acylcarnitines due to ischemia in brain tissue of the middle cerebral artery occlusion (MCAO) stroke model. Further, we estimate activities of carnitine transporting enzymes and demonstrate disruptions in the carnitine shuttle system that affects the β-oxidation in the mitochondria. Our results show the importance for quantitative monitoring of metabolite distributions in distinct tissue regions to understand cell compensation mechanisms involved in handling damage caused by stroke.
| S-EPMC9968086 | biostudies-literature
Project description:The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific knockout of carnitine palmitoyltransferase 2 (Cpt2L-/-), an obligate step in mitochondrial long-chain fatty acid β-oxidation. Surprisingly, Cpt2L-/- mice survived the perinatal period and a 24hr fast with sufficient blood glucose. The loss of hepatic fatty acid oxidation resulted in a significant loss in circulating ketones that remained unaltered by fasting. Fasting induced serum dyslipidemia, hepatic steatosis and adaptations in hepatic and systemic oxidative gene expression in Cpt2L-/- mice to maintain systemic energy homeostasis. Alternatively, feeding a ketogenic diet resulted in severe hepatomegaly, liver damage and death within one week with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting. In this dataset, we include the expression data obtained from dissected mouse liver from mice fasted for 24 hours with and without the deletion of carnitine palmitoyltransferase 2 (i.e. hepatocytes unable to beta-oxidize long chain fatty acids in mitochondria). WildType and KnockOut mice were fasted for 24 hours. Three biologic replicates were compared per class, thus six mice.
2016-06-16 | E-GEOD-76079 | biostudies-arrayexpress
Project description:The Mycobacterium tuberculosis acyl-CoA carboxylases provide the building blocks for de novo fatty acid biosynthesis by fatty acid synthase (FAS) I and for the elongation of FAS I end-products by the FAS II complex to produce meromycolic acids. M. tuberculosis genome contains three biotin carboxylase subunits (AccA1-3) and 6 carboxyltransferase subunits (AccD1-6) of which AccD6 is located in a genetic locus that contains members of the FAS II complex. We found by microarray and quantitative real-time RT-PCR analysis that the transcripts of AccA3, AccD4, AccD5 and AccD6 are expressed at high levels during exponential growth phases of M. tuberculosis in vitro. Keywords: Time course, developmental stages
2006-10-07 | GSE5977 | GEO
Project description:The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific knockout of carnitine palmitoyltransferase 2 (Cpt2L-/-), an obligate step in mitochondrial long-chain fatty acid β-oxidation. Surprisingly, Cpt2L-/- mice survived the perinatal period and a 24hr fast with sufficient blood glucose. The loss of hepatic fatty acid oxidation resulted in a significant loss in circulating ketones that remained unaltered by fasting. Fasting induced serum dyslipidemia, hepatic steatosis and adaptations in hepatic and systemic oxidative gene expression in Cpt2L-/- mice to maintain systemic energy homeostasis. Alternatively, feeding a ketogenic diet resulted in severe hepatomegaly, liver damage and death within one week with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting. In this dataset, we include the expression data obtained from dissected mouse liver from mice fasted for 24 hours with and without the deletion of carnitine palmitoyltransferase 2 (i.e. hepatocytes unable to beta-oxidize long chain fatty acids in mitochondria).
2016-06-16 | GSE76079 | GEO