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The anti-metastatic effect of pyruvate dehydrogenase kinase 4 inhibition in bladder cancer via p-AKT, p-ERK, p-Src and p-JNK pathway

ABSTRACT: To confirm the anti-metastatic effect in bladder cancer cell lines, the PDK4 gene was knocked down and phosphorylated protein changes were compared through LC-MS/MS analysis.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Urinary Bladder Cancer

SUBMITTER: Eunji Sung

LAB HEAD: SangKyu Lee

PROVIDER: PXD035005 | Pride | 2023-03-10

REPOSITORIES: Pride

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Anti-Metastatic Effect of Pyruvate Dehydrogenase Kinase 4 Inhibition in Bladder Cancer via the ERK, SRC, and JNK Pathways.

Lee Eun Hye EH Chung Jae-Wook JW Sung Eunji E Yoon Bo Hyun BH Jeon Minji M Park Song S Chun So Young SY Lee Jun Nyung JN Kim Bum Soo BS Kim Hyun Tae HT Kim Tae Hwan TH Choi Seock Hwan SH Yoo Eun Sang ES Kwon Tae Gyun TG Kang Ho Won HW Kim Wun-Jae WJ Yun Seok Joong SJ Lee Sangkyu S Ha Yun-Sok YS

International journal of molecular sciences 20221031 21

Bladder cancer is a common global cancer with a high percentage of metastases and high mortality rate. Thus, it is necessary to identify new biomarkers that can be helpful in diagnosis. Pyruvate dehydrogenase kinase 4 (PDK4) belongs to the PDK family and plays an important role in glucose utilization in living organisms. In the present study, we evaluated the role of PDK4 in bladder cancer and its related protein changes. First, we observed elevated PDK4 expression in high-grade bladder cancers. ...[more]

PMID: 36362028

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pyruvate dehydrogenase kinase 4 regulate mitochondrial dynamics

Project description:Mitochondrial dynamics provides cells with the flexibility required to adapt and respond to mitochondrial toxins, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here we show that pyruvate dehydrogenase kinase 4 (PDK4) is required for cells to undergo rapid mitochondrial fragmentation when challenged with toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of stress. Phosphoproteomic screen for PDK4 substrates identified cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 to promote mitochondrial fission. PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics, supports cancer cell growth and revealed PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial dynamics at the interface between cellular bioenergetics and mitochondrial dynamics

2023-03-10 | PXD028379 | Pride

Characterization of RAS/RAF/ERK signal cascade as a novel regulating factor in alpha-amanitin-induced liver injury

Project description:The well-known hepatotoxicity mechanism resulting from alpha-amanitin (-AMA) exposure arises from RNA polymerase II (RNAP II) inhibition. RNAP Ⅱ inhibition occurs through the dysregulation of mRNA synthesis. However, the signaling pathways in hepatocytes that arise from -AMA have not yet been fully elucidated. Here, we identified that the RAS/RAF/ERK signaling pathway was activated through quantitative phosphoproteomic and molecular biological analyses. Bioinformatics analysis showed that AMA exposure increased protein phosphorylation in a time-dependent AMA AMA exposure. In addition, phosphorylation increased not only the components of the ERK signaling pathway but also U2AF65 and SPF45, known splicing factors. Therefore, we propose a novel mechanism of -AMA as follows. The RAS/RAF/ERK signaling pathway involved in aberrant splicing events is activated by -AMA exposure followed by aberrant splicing events leading to cell death.

2023-03-11 | PXD035758 | Pride

Characterization of RAS/RAF/ERK signal cascade as a novel regulating factor in alpha-amanitin-induced liver injury

2023-03-11 | PXD035817 | Pride

Expression data from PDK4 overexpressing (Ad-PDK4 infected) and control (Ad-control infected) mouse liver

Project description:We identified PDK4 as a gene with adaptive transcriptional response to chemical stress. Although PDK4 is an energy resource regulator induced by starvation, expression of other fasting-inducible genes was unaffected, indicating additional physiological role of PDK4 for liver adaptation to the chemical stress. We used microarrays to determine genes with altered transcriptional level by PDK4 overexpression. Mice were infected with Ad-control (empty adenovirus vector) or Ad-PDK4 (PDK4 overexpressing adenovirus vector) at a dose of 10^9 PFU/mouse by tail vein injection. 3 days after the infection, mice were sacrificed for RNA preparation from the liver. Ad-control infected = 4, Ad-PDK4 infected = 3. Specimens from mice of each group were pooled, and 10 ug RNA from each pool was used for cRNA synthesis.

2010-12-25 | E-GEOD-22534 | biostudies-arrayexpress

Ethyl pyruvate attenuates formalin-induced inflammatory nociception by inhibiting neuronal ERK phosphorylation.

Project description: Not available

| S-EPMC3472237 | biostudies-literature

Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease

Project description:Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in mitochondria-associated ER membranes (MAMs) mediates Ca2+ accumulation-induced mitochondrial dysfunction in ALD via the formation of glucose-regulated protein 75 (GRP75)-mediated MAM Ca2+-channeling (MCC) complex. Unbiased transcriptomic analysis reveals pyruvate dehydrogenase kinase 4 (PDK4) as a prominently inducible MAM kinase in ALD. Additional mass spectrometry analysis unveils the critical role of PDK4 in promoting alcohol-induced MCC complex formation and mitochondrial dysfunction by phosphorylating GRP75. Non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced mitochondrial Ca2+ accumulation and dysfunction. Conversely, ectopic induction of MAM formation in PDK4-deficient mice abrogate the protective effect in alcohol-induced liver injury. Together, our study defines the mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.

2023-05-10 | PXD039478 | Pride

Short-term mild temperature-stress-induced alterations in C. elegans phosphoproteome

Project description:Exposure to mild early-life stresses can slow down the aging process, in which protein phosphorylation might be an essential regulator. Currently, the understanding of phosphorylation-based regulatory networks under mild early-life stress remains elusive. Herein, we systematically analyzed the phosphoproteomes of C. elegans, which were treated with three kinds of mild temperature (15°C, 20°C, and 25°C) from two different short-term groups (10 min and 60 min). By utilizing iTRAQ-based quantitative phosphoproteomic approach, a total of 18187 phosphorylation sites from 3330 proteins were identified. Volcano plots illustrated that the phosphorylation abundance of 374 proteins (15°C) and 347 proteins (25°C), were significantly changed, respectively. Gene ontology, KEGG pathway and protein-protein interaction network analysis revealed that these phosphoproteins were mainly involved in metabolism, translation, development, and lifespan determination. Motif analysis of kinase substrates suggested that MAPK, CK and CAMK were most likely involved in the adaption processes. Moreover, 16 and 14 aging-regulated proteins underwent phosphorylation modifications under the mild stress of 15°C and 25°C, respectively, indicating these proteins might be important for maintaining long-term health. Further experiments of lifespan confirmed that the candidate phosphoproteins, e.g.; EGL-27, XNP-1, and GTBP-1 could regulate lifespan at 15°C, 20°C, and 25°C, and showed increased tolerance to heat and oxidative stresses. In summary, our findings provided a wealth of datasets to better understand the phosphorylation mechanism of mild early-life stresses in C. elegans.

2020-09-17 | PXD021081 | Pride

Expression data from PDK4 overexpressing (Ad-PDK4 infected) and control (Ad-control infected) mouse liver

2010-12-25 | GSE22534 | GEO

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Project description:Prostate cancer has a broad spectrum of clinical behavior, hence biomarkers are urgently needed for risk stratification. We previously described the protective effect of signal transducer and activator of transcription 3 (STAT3) in a prostate cancer mouse model. We now show the importance of STAT3-regulated metabolic functions and explain their influence on aggressive prostate cancer. By utilizing a gene co-expression network in addition to laser microdissected proteomics from human and murine FFPE samples, we established a workflow that facilitates the discovery of new biomarkers. We thereby identified the protective effect of pyruvate dehydrogenase kinase 4 (PDK4) in prostate cancer. PDK4 is a key regulator of the citrate cycle and low PDK4 is significantly associated with disease recurrence.

2020-04-22 | PXD014251 | Pride

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Project description:The oxidation of methionine side chains has emerged as an important posttranslational modification of proteins. A diverse array of low-throughput and targeted studies have suggested that the oxidation of methionine residues in select proteins can have diverse impacts on cell physiology, ranging from detrimental effects on protein structure and stability to functional roles in cell signaling. Despite its importance, the large-scale investigation of methionine oxidation in a complex matrix, such as the cellular proteome has been historically hampered by technical limitations. Herein we report a methodology, Methionine Oxidation by Blocking (MobB), that allows for accurate and precise quantification of low levels of methionine oxidation typically observed in vivo. To demonstrate the utility of this methodology, we applied MobB to the brain tissues of young (6 m.o.) and old (20 m.o.) mice and identified over 280 novel sites for in vivo methionine oxidation. We further demonstrated that oxidation stoichiometries for specific methionine residues are highly consistent between individual animals and methionine sulfoxides are enriched in clusters of functionally related gene products including membrane and extracellular proteins. However, we did not detect significant changes in methionine oxidation in brains of old mice, suggesting that oxidation levels are highly regulated during the course of aging.

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