Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPARγ-mediated pathway in bladder cancer

Cheng, Songtao; Wang, Gang; Wang, Yejinpeng; Cai, Liwei; Qian, Kaiyu; Ju, Lingao; Li, Xuefeng; Xiao, Yu; Wang, Xinghuan

doi:10.1042/cs20190587

Cited by 93 publications

(76 citation statements)

References 54 publications

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“…Peroxisome proliferator-activated receptors (PPARs), which are members of the nuclear receptor superfamily, can be divided into three subtypes: PPARα, PPARβ and PPARγ [5]. Our results and previous studies showed that PPARγ plays a significant role in the occurrence and progression of bladder cancer through regulation of proliferation, apoptosis, metastasis, and reactive oxygen species (ROS) and lipid metabolism [6][7][8][9][10]. The purpose of this paper is to provide an overview of the role, function and potential molecular mechanisms of PPARγ in bladder cancer.…”

Section: Introductionsupporting

confidence: 51%

“…The mRNA expression of CPT1A was significantly higher in MIBC patients than in NMIBC patients [133]. In vivo and in vitro experiments by our group showed that etomoxir, a specific inhibitor of CPT1A, inhibited bladder cell proliferation and induced cell cycle arrest in G0/G1 phase by activating the PPARγ signaling pathway [6]. In addition, our results also revealed that simvastatin, an inhibitor of cholesterol synthesis, reduced intracellular cholesterol levels and inhibited cell proliferation and migration through the PPARγ signaling pathway [10].…”

Section: Discussionmentioning

confidence: 83%

“…Our group collected bladder cancer tissue and normal tissue for transcriptomics data analysis. The results revealed that the PPAR signaling pathway is closely related to bladder cancer and may be involved in regulating lipid metabolism [6,10]. Jin et al reported 12 differential metabolites that contributed to the distinction between the BCa and control groups and many of them were involved in fatty acid β-oxidation [88].…”

Section: Discussionmentioning

confidence: 99%

“…The results revealed that the PPAR signaling pathway mattered greatly in fatty acid/lipid metabolism in bladder cancer [10]. Etomoxir, a fatty acid β-oxidation inhibitor, activates PPARγ-mediated signaling, resulting in the cell cycle arrest in BCa cells [6]. Moreover, intracellular cholesterol and fatty acids are important components of the cell membrane [94], especially in the membrane domains, which are enriched with lipid rafts and are important in cell proliferation and biological metabolism [95,96].…”

Section: Pparγ and Lipid Metabolismmentioning

confidence: 99%

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The role and function of PPARγ in bladder cancer

Peng¹,

Wang²,

Cheng³

et al. 2020

J. Cancer

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Peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear receptor superfamily, participates in multiple physiological and pathological processes. Extensive studies have revealed the relationship between PPARγ and various tumors. However, the expression and function of PPARγ in bladder cancer seem to be controversial. It has been demonstrated that PPARγ affects the occurrence and progression of bladder cancer by regulating proliferation, apoptosis, metastasis, and reactive oxygen species (ROS) and lipid metabolism, probably through PPARγ-SIRT1 feedback loops, the PI3K-Akt signaling pathway, and the WNT/β-catenin signaling pathway. Considering the frequent relapses after chemotherapy, some researchers have focused on the relationship between PPARγ and chemotherapy sensitivity in bladder cancer. Moreover, the feasibility of PPARγ ligands as potential therapeutic targets for bladder cancer has been uncovered. Taken together, this review summarizes the relevant literature and our findings to explore the complicated role and function of PPARγ in bladder cancer.

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Section: Introductionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Pparγ and Lipid Metabolismmentioning

confidence: 99%

See 2 more Smart Citations

The role and function of PPARγ in bladder cancer

Peng¹,

Wang²,

Cheng³

et al. 2020

J. Cancer

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“…Increased glycolysis under normoxic conditions (Warburg effect), glutamine metabolism, and lipid metabolism are the main characteristics of malignant tumors. Previous studies have indicated that metabolic pathways play critical roles in the occurrence and progression of BC [4][5][6]. Therefore, it is indispensable to explore more potential reliable and valuable biomarkers, especially metabolism-associated genes (MAGs), to predict disease development and prognosis in BC patients.…”

Section: Introductionmentioning

confidence: 99%

Identification of Metabolism-associated Genes and Construction of a Prognostic Signature in Bladder Cancer

Shen

Liu

Wang

et al. 2020

Preprint

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Background Bladder cancer (BC) is a commonly diagnosed malignant tumor in the urinary system, with a high morbidity and recurrence rate. Current studies indicated that metabolism-associated genes (MAGs) having critical roles in the etiology of BC. The present study aims to identify differentially expressed MAGs and construct a MAGs prognostic risk signature in BC by using The Cancer Genome Atlas (TCGA) database and proteomics data. Methods RNA-sequence data from the TCGA database and proteomics were used to identify differentially expressed MAGs and construct a prognostic MAGs signature in BC. Subsequently, survival analysis and nomogram were used to evaluate the prognostic and predictive value of the MAGs model in BC. RNA isolation and reverse transcription‑quantitative PCR (RT-qPCR) was further performed to investigate the expression levels of MAGs in BC cell lines and explore the relationship between MAGs and M2 tumor associated macrophages (TAMs) secreted TGF-beta 1 in BC. Results A total of 23 differentially expressed MAGs were identified and five MAGs were finally used to construct a MAGs based signature. Survival analysis revealed that the MAGs based signature was closely correlated with the survival outcomes of patients with BC. A nomogram with the MAGs based signature risk score and clinical features also constructed to facilitate the individualized prediction of BC patients. RT-qPCR showed that four MAGs were significantly elevated and the expression levels of three MAGs were positively correlated with M2 TAM secreted TGF-β1 in T24 cells. Conclusions Our study identified novel prognostic MAGs and constructed a MAGs based signature, which can be used as an independent signature in evaluating the prognosis of patients with BC. Furthermore, M2 TAMs may promote the expression of three MAGs via TGF-β1 signaling pathway. Further clinical trials and experimental exploration are needed to validate our observations in BC.

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NAT10: An RNA cytidine transferase regulates fatty acid metabolism in cancer cells

Dalhat

Mohammed

Alkhatabi

et al. 2022

Clinical & Translational Med

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Background N‐4 cytidine acetylation (ac4C) is an epitranscriptomics modification catalyzed by N‐acetyltransferase 10 (NAT10); important for cellular mRNA stability, rRNA biogenesis, cell proliferation and epithelial to mesenchymal transition (EMT). However, whether other crucial pathways are regulated by NAT10‐dependent ac4C modification in cancer cells remains unclear. Therefore, in this study, we explored the impact of NAT10 depletion in cancer cells using unbiased RNA‐seq. Methods High‐throughput sequencing of knockdown NAT10 in cancer cells was conducted to identify enriched pathways. Acetylated RNA immunoprecipitation‐seq (acRIP‐seq) and RIP‐PCR were used to map and determine ac4C levels of RNA. Exogenous palmitate uptake assay was conducted to assess NAT10 knockdown cancer cells using Oil Red O staining and lipid content analysis. Gas‐chromatography–tandem mass spectroscopy (GC/MS) was used to perform untargeted lipidomics. Results High‐throughput sequencing of NAT10 knockdown in cancer cells revealed fatty acid (FA) metabolism as the top enriched pathway through the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis in differentially downregulated genes. FA metabolic genes such as ELOLV6, ACSL1, ACSL3, ACSL4, ACADSB and ACAT1 were shown to be stabilised via NAT10‐dependent ac4C RNA acetylation. Additionally, NAT10 depletion was shown to significantly reduce the levels of overall lipid content, triglycerides and total cholesterol. Further, NAT10 depletion in palmitate‐loaded cancer cells showed decrease in ac4C levels across the RNA transcripts of FA metabolic genes. In untargeted lipidomics, 496 out of 2 279 lipids were statistically significant in NAT10 depleted cancer cells, of which pathways associated with FA metabolism are the most enriched. Conclusions Conclusively, our results provide novel insights into the impact of NAT10‐mediated ac4C modification as a crucial regulatory factor during FA metabolism and showed the benefit of targeting NAT10 for cancer treatment.

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Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPARγ-mediated pathway in bladder cancer

Cited by 93 publications

References 54 publications

The role and function of PPARγ in bladder cancer

The role and function of PPARγ in bladder cancer

Identification of Metabolism-associated Genes and Construction of a Prognostic Signature in Bladder Cancer

NAT10: An RNA cytidine transferase regulates fatty acid metabolism in cancer cells

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