GAMT joins the p53 network: Branching into metabolism

Ide, Takao; Chu, Kengyeh K.; Aaronson, Stuart A.; Lee, Sam W.

doi:10.4161/cc.9.9.11473

Cited by 23 publications

(17 citation statements)

References 47 publications

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“…The TP53-dependent regulation of fatty acid oxidation pathway occurs by activation of GAMT [28]. Gluconeogenesis, a reverse glycolytic pathway, generates glucose from small noncarbohydrate precursors.…”

Section: Discussionmentioning

confidence: 99%

TP53 mutation hits energy metabolism and increases glycolysis in breast cancer

et al. 2016

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Promising new hallmarks of cancer is alteration of energy metabolism that involves molecular mechanisms shifting cancer cells to aerobe glycolysis. Our goal was to evaluate the correlation between mutation in the commonly mutated tumor suppressor gene TP53 and metabolism. We established a database comprising mutation and RNA-seq expression data of the TCGA repository and performed receiver operating characteristics (ROC) analysis to compare expression of each gene between TP53 mutated and wild type samples. All together 762 breast cancer samples were evaluated of which 215 had TP53 mutation. Top up-regulated metabolic genes include glycolytic enzymes (e.g. HK3, GPI, GAPDH, PGK1, ENO1), glycolysis regulator (PDK1) and pentose phosphate pathway enzymes (PGD, TKT, RPIA). Gluconeogenesis enzymes (G6PC3, FBP1) were down-regulated. Oxygen consumption and extracellular acidification rates were measured in TP53 wild type and mutant breast cell lines with a microfluorimetric analyzer. Applying metabolic inhibitors in the presence and absence of D-glucose and L-glutamine in cell culture experiments resulted in higher glycolytic and mitochondrial activity in TP53 mutant breast cancer cell lines. In summary, TP53 mutation influences energy metabolism at multiple levels. Our results provide evidence for the synergistic activation of multiple hallmarks linking to these the mutation status of a key driver gene.

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Section: Discussionmentioning

confidence: 99%

TP53 mutation hits energy metabolism and increases glycolysis in breast cancer

et al. 2016

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“…Lower levels of p53 and downstream p21 Cip-1 were induced in doxorubicin-resistant MCF-7 cells which also contain activated Akt-1[99]. p53 plays key roles in the regulation of cellular senescence [38-40,43-46,110-120], DNA damage response [121-123], cell cycle progression [124-143], chromosome dynamics [144-146], apoptosis [147-151], sensitivity to chemotherapy [152-154], radiotherapy [107,155] tumorigenesis and metastasis [53,156-158], metabolism [159-161], cellular redox [41,162], hypoxia [61,75,136,163,164], autophagy [49,165,166] and aging [167] as well as other important biological processes. Often some of the purported functions of p53 are overlapping and even sometimes contradictory.…”

Section: Discussionmentioning

confidence: 99%

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

et al. 2011

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Escape from cellular senescence induction is a potent mechanism for chemoresistance. Cellular senescence can be induced in breast cancer cell lines by the removal of estrogen signaling with tamoxifen or by the accumulation of DNA damage induced by the chemotherapeutic drug doxorubicin. Long term culturing of the hormone-sensitive breast cancer cell line MCF-7 in doxorubicin (MCF-7/DoxR) reduced the ability of doxorubicin, but not tamoxifen, to induce senescence. Two pathways that are often upregulated in chemo- and hormonal-resistance are the PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways. To determine if active Akt-1 and Raf-1 can influence drug-induced senescence, we stably introduced activated ΔAkt-1(CA) and ΔRaf-1(CA) into drug-sensitive and doxorubicin-resistant cells. Expression of a constitutively-active Raf-1 construct resulted in higher baseline senescence, indicating these cells possessed the ability to undergo oncogene-induced-senescence. Constitutive activation of the Akt pathway significantly decreased drug-induced senescence in response to doxorubicin but not tamoxifen in MCF-7 cells. However, constitutive Akt-1 activation in drug-resistant cells containing high levels of active ERK completely escaped cellular senescence induced by doxorubicin and tamoxifen. These results indicate that up regulation of the Ras/PI3K/PTEN/Akt/mTOR pathway in the presence of elevated Ras/Raf/MEK/ERK signaling together can contribute to drug-resistance by diminishing cell senescence in response to chemotherapy. Understanding how breast cancers containing certain oncogenic mutations escape cell senescence in response to chemotherapy and hormonal based therapies may provide insights into the design of more effective drug combinations for the treatment of breast cancer.

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“…While inhibiting mTOR, p53 suppressed p21-induced senescence, causing quiescence instead [27]. p53 affects autophagy and metabolic pathways not only via inhibition of mTOR but also probably independently from mTOR [22,28-35]. We use the term mTOR-centric network to encompass not only upstream and downstream but also parallel and TOR-like pathways [36].…”

Section: Introductionmentioning

confidence: 99%

DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence

Leontieva

Blagosklonny

2010

Aging

149

153

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When the cell cycle is arrested, growth-promoting pathways such as mTOR (Target of Rapamycin) drive cellular senescence, characterized by cellular hyper-activation, hypertrophy and permanent loss of the proliferative potential. While arresting cell cycle, p53 (under certain conditions) can inhibit the mTOR pathway. Senescence occurs when p53 fails to inhibit mTOR. Low concentrations of DNA-damaging drugs induce p53 at levels that do not inhibit mTOR, thus causing senescence. In quiescence caused by serum starvation, mTOR is deactivated. This predicts that induction of p53 will not cause senescence in such quiescent cells. Here we tested this prediction. In proliferating normal cells, etoposide caused senescence (cells could not resume proliferation after removal of etoposide). Serum starvation prevented induction of senescence, but not of p53, by etoposide. When etoposide was removed, such cells resumed proliferation upon addition of serum. Also, doxorubicin did not cause senescent morphology in the absence of serum. Re-addition of serum caused mTOR-dependent senescence in the presence of etoposide or doxorubicin. Also, serum-starvation prevented senescent morphology caused by nutlin-3a in MCF-7 and Mel-10 cells. We conclude that induction of p53 does not activate the senescence program in quiescent cells. In cells with induced p53, re-activation of mTOR by serum stimulation causes senescence, as an equivalent of cellular growth.

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GAMT joins the p53 network: Branching into metabolism

Cited by 23 publications

References 47 publications

TP53 mutation hits energy metabolism and increases glycolysis in breast cancer

TP53 mutation hits energy metabolism and increases glycolysis in breast cancer

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence

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