Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism

Reynolds, Miriam R.; Clem, Brian F.

doi:10.1515/hsz-2014-0307

Cited by 5 publications

(6 citation statements)

References 39 publications

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“…These findings suggest that PPARγ agonist could induce c‐Myc proteasomal‐dependent degradation, while it is independent of PPARγ. Our results showed that overexpression of PPARγ reduced c‐Myc protein level, and agonist PIOG significantly enhanced PPARγ‐mediated c‐Myc degradation in colon cancer cells, suggesting that PIOG induced c‐Myc degradation in a PPARγ‐dependent manner, which is different other reports that agonists induced c‐Myc degradation independent of PPARγ 17,50 . Previous reports suggest that PPARγ could act as E3 ligase to induce substrates ubiquitination and degradation 18,24,51,52 .…”

Section: Discussioncontrasting

confidence: 64%

“…13 However, PPARγ agonist troglitazone reduced c-Myc protein level in lung cancer cell line, but proteasome inhibitor MG132 reversed this event, which is independent of PPARγ. 50 Similarly, PPARγ agonist troglitazone reduced c-Myc protein and gene level independent of PPARγ activity in C4-2 cells, and proteasome inhibitor MG132 can reverse this event. 17 These findings suggest that PPARγ agonist could induce c-Myc proteasomaldependent degradation, while it is independent of PPARγ.…”

Section: Discussionmentioning

confidence: 97%

“…PPARγ agonist PIOG inhibits fibroblast‐like synoviocyte proliferation and migration, which is associated with reduced c‐Myc gene and protein expression 13 . However, PPARγ agonist troglitazone reduced c‐Myc protein level in lung cancer cell line, but proteasome inhibitor MG132 reversed this event, which is independent of PPARγ 50 . Similarly, PPARγ agonist troglitazone reduced c‐Myc protein and gene level independent of PPARγ activity in C4‐2 cells, and proteasome inhibitor MG132 can reverse this event 17 .…”

Section: Discussionmentioning

confidence: 99%

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PPARγ agonist inhibits c‐Myc‐mediated colorectal cancer tumor immune escape

Che

Chen

et al. 2023

J of Cellular Biochemistry

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As a master transcription factor, c‐Myc plays an important role in promoting tumor immune escape. In addition, PPARγ (peroxisome proliferator‐activated receptor γ) regulates cell metabolism, inflammation, and tumor progression, while the effect of PPARγ on c‐Myc‐mediated tumor immune escape is still unclear. Here we found that cells treated with PPARγ agonist pioglitazone (PIOG) reduced c‐Myc protein expression in a PPARγ‐dependent manner. qPCR analysis showed that PIOG had no significant effect on c‐Myc gene levels. Further analysis showed that PIOG decreased c‐Myc protein half‐life. Moreover, PIOG increased the binding of c‐Myc to PPARγ, and induced c‐Myc ubiquitination and degradation. Importantly, c‐Myc increased PD‐L1 and CD47 immune checkpoint protein expression and promoted tumor immune escape, while PIOG inhibited this event. These findings suggest that PPARγ agonist inhibited c‐Myc‐mediated tumor immune escape by inducing its ubiquitination and degradation.

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Section: Discussioncontrasting

confidence: 64%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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PPARγ agonist inhibits c‐Myc‐mediated colorectal cancer tumor immune escape

Che

Chen

et al. 2023

J of Cellular Biochemistry

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“…A number of studies have suggested that PPARa and PPARg activation could be used as a target to prevent or treat cancer through both PPAR-dependent and -independent mechanisms (28). In particular, in terms of glutamine metabolism, the PPARg agonist Troglitazone has been shown to exhibit antitumor activity by suppressing glutamine uptake and incorporation into the TCA cycle (29). By contrast, there is no broad consensus concerning the role of PPARd in carcinogenesis (28).…”

Section: Discussionmentioning

confidence: 99%

PPARδ Reprograms Glutamine Metabolism in Sorafenib-Resistant HCC

Kim

Choi

Park

et al. 2017

Molecular Cancer Research

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The tyrosine kinase inhibitor sorafenib is the only therapeutic agent approved for the treatment of advanced hepatocellular carcinoma (HCC), but acquired resistance to sorafenib is high. Here, we report metabolic reprogramming in sorafenib-resistant HCC and identify a regulatory molecule, peroxisome proliferator-activated receptor-δ (PPARδ), as a potential therapeutic target. Sorafenib-resistant HCC cells showed markedly higher glutamine metabolism and reductive glutamine carboxylation, which was accompanied by increased glucose-derived pentose phosphate pathway and glutamine-derived lipid biosynthetic pathways and resistance to oxidative stress. These glutamine-dependent metabolic alterations were attributed to PPARδ, which was upregulated in sorafenib-resistant HCC cells and human HCC tissues. Furthermore, PPARδ contributed to increased proliferative capacity and redox homeostasis in sorafenib-resistant HCC cells. Accordingly, inhibiting PPARδ activity reversed compensatory metabolic reprogramming in sorafenib-resistant HCC cells and sensitized them to sorafenib. Therefore, targeting compensatory metabolic reprogramming of glutamine metabolism in sorafenib-resistant HCC by inhibiting PPARδ constitutes a potential therapeutic strategy for overcoming sorafenib-resistance in HCC. This study provides novel insight into the mechanism underlying sorafenib resistance and a potential therapeutic strategy targeting PPARδ in advanced hepatocellular carcinoma. .

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“…Our data also demonstrated that PPAR is a prospective signaling pathway in response to lower levels of dietary protein. PPARs are a group of nuclear receptor proteins that function as transcription factors that regulate gene expression, with essential roles in the regulation of cellular differentiation [ 44 ], development [ 45 ], and metabolism [ 46 ]. Our in vitro studies revealed that 4× AA significantly enhanced the gene expression of PPARγ and IGF-1 compared with 1× AA in porcine primary hepatocytes and human HepG2 cells.…”

Section: Discussionmentioning

confidence: 99%

Dietary protein-induced hepatic IGF-1 secretion mediated by PPARγ activation

Wan

Wang

et al. 2017

PLoS ONE

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Dietary protein or amino acid (AA) is a crucial nutritional factor to regulate hepatic insulin-like growth factor-1 (IGF-1) expression and secretion. However, the underlying intracellular mechanism by which dietary protein or AA induces IGF-1 expression remains unknown. We compared the IGF-1 gene expression and plasma IGF-1 level of pigs fed with normal crude protein (CP, 20%) and low-protein levels (LP, 14%). RNA sequencing (RNA-seq) was performed to detect transcript expression in the liver in response to dietary protein. The results showed that serum concentrations and mRNA levels of IGF-1 in the liver were higher in the CP group than in the LP group. RNA-seq analysis identified a total of 1319 differentially expressed transcripts (667 upregulated and 652 downregulated), among which the terms “oxidative phosphorylation”, “ribosome”, “gap junction”, “PPAR signaling pathway”, and “focal adhesion” were enriched. In addition, the porcine primary hepatocyte and HepG2 cell models also demonstrated that the mRNA and protein levels of IGF-1 and PPARγ increased with the increasing AA concentration in the culture. The PPARγ activator troglitazone increased IGF-1 gene expression and secretion in a dose dependent manner. Furthermore, inhibition of PPARγ effectively reversed the effects of the high AA concentration on the mRNA expression of IGF-1 and IGFBP-1 in HepG2 cells. Moreover, the protein levels of IGF-1 and PPARγ, as well as the phosphorylation of mTOR, significantly increased in HepG2 cells under high AA concentrations. mTOR phosphorylation can be decreased by the mTOR antagonist, rapamycin. The immunoprecipitation results also showed that high AA concentrations significantly increased the interaction of mTOR and PPARγ. In summary, PPARγ plays an important role in the regulation of IGF-1 secretion and gene expression in response to dietary protein.

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Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism

Cited by 5 publications

References 39 publications

PPARγ agonist inhibits c‐Myc‐mediated colorectal cancer tumor immune escape

PPARγ agonist inhibits c‐Myc‐mediated colorectal cancer tumor immune escape

PPARδ Reprograms Glutamine Metabolism in Sorafenib-Resistant HCC

Dietary protein-induced hepatic IGF-1 secretion mediated by PPARγ activation

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