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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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			Action	DRS
	20210503_TiO2_J82_1_test.raw	Raw
	20210506_TiO2_J82_1-2.raw	Raw
	20210506_TiO2_J82_2-1.raw	Raw
	20210506_TiO2_J82_2-2.raw	Raw
	20210507_TiO2_J82_2-1.raw	Raw

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Publications

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

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

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

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

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

2010-12-25 | GSE22534 | GEO

STAT3-dependent systems-level analysis reveals PDK4 to be associated with favorable outcome in primary prostate cancer.

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

Accurate proteome-wide measurement of methionine oxidation in aging mouse brains

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.

2022-05-23 | PXD031238 | Pride

Transcriptomic landscape of mouse pulmonary alveolar cells upon chronological aging and/or anti-senescence intervention

Project description:As a critical hallmark of senescent cells, the senescence-associated secretory phenotype (SASP) develops over the course of chronological aging and in diverse age-related conditions, and is a key driver of chronic inflammation and age-associated phenotypes. For years, the identification, characterization and pharmacological targeting of senescent cells have gained substantial attention in the field of aging and age-related pathologies. Pyruvate dehydrogenase kinase 4 (PDK4) is an important mitochondrial matrix enzyme in cellular energy regulation, and drives the metabolic reprogramming of mammalian cells towards a Warburg-like effect. Upregulation of PDK4 is responsible for enhanced production of lactate in the tissue microenvironment of aged organisms, potentially causing chronic inflammation and contributing to accelerated aging. Targeting PDK4 holds the potential to prevent lactate accumulation, minimize tissue damage and postpone senescence-associated systemic aging. Here we profiled the genome-wide expression of cells (mainly fibroblasts) in mouse pulmonary alveolus, with the assistance of laser capture microdissection (LCM) of primary lung tissues. Animals were allowed to naturally age, or subject to treatment by PDK4-IN (an anthraquinone derivative, PDK4 inhibitor). These data may provide a baseline to further determine the effects of lactate reduction by PDK4-specific targeting on cellular senescence, tissue homeostasis, and explore the wide implications of PDK4 expression in organismal aging and age-related morbidity.

2023-09-05 | GSE217808 | GEO

Transcriptomic landscape of human primary stromal cells upon chemotherapeutic and/or PDK4-specific intervention

Project description:Cellular senescence is a response elicited by acute or chronic damage signals. In humans, senescent cells accumulate in multiple tissues at different rates, from 2- to 20-fold when comparing young (<35 years) to old (>65 years) healthy donors. The pathogenic role of cellular senescence in diverse age-related diseases can be largely explained by the senescence-associated secretory phenotype (SASP). Senescent cells display changes in mitochondrial activity with increased ATP production and high lactate production, which are partially correlated with upregulation of pyruvate dehydrogenase kinase 4 (PDK4), an inhibitor of mitochondrial pyruvate dehydrogenase. We used a genotoxic agent, bleomycin, and/or a PDK4-targeting chemical, PDK4-IN, to treat human primary stromal cells and determined the influence of PDK4 inhibition on the transcriptomic expression profile of senescent cells. The data allow to disclose the importance of PDK4 activity in development of senescence-associated phenotypes, particularly the SASP.

2023-09-05 | GSE222279 | GEO

Cardiomyocyte Pdk4 response is associated with metabolic maladaptation in aging

Project description:Pyruvate Dehydrogenase Kinase 4 (Pdk4) is a pyruvate dehydrogenase inhibiton gene that strongly regulates metabolism. We studied the expression of Pdk4 in the young and aged mouse heart in both healthy conditions and after ischemic insult.

2023-01-31 | GSE213080 | GEO

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