The non-essential amino acid serine supports several metabolic processes that are crucial for the growth and survival of proliferating cells, including protein, amino acid and glutathione synthesis. ...As an important one-carbon donor to the folate cycle, serine contributes to nucleotide synthesis, methylation reactions and the generation of NADPH for antioxidant defence. Many cancer cells are highly dependent on serine, a trait that provides several novel therapeutic opportunities, either through the inhibition of de novo serine synthesis or by limiting the availability or uptake of exogenous serine.
Many different types of cancer show a high incidence of TP53 mutations, leading to the expression of mutant p53 proteins. There is growing evidence that these mutant p53s have both lost wild-type p53 ...tumor suppressor activity and gained functions that help to contribute to malignant progression. Understanding the functions of mutant p53 will help in the development of new therapeutic approaches that may be useful in a broad range of cancer types.
While the tumor suppressor functions of p53 have long been recognized, the contribution of p53 to numerous other aspects of disease and normal life is only now being appreciated. This burgeoning ...range of responses to p53 is reflected by an increasing variety of mechanisms through which p53 can function, although the ability to activate transcription remains key to p53's modus operandi. Control of p53's transcriptional activity is crucial for determining which p53 response is activated, a decision we must understand if we are to exploit efficiently the next generation of drugs that selectively activate or inhibit p53.
Eukaryotic cells have developed complex systems to regulate the production and response to reactive oxygen species (ROS). Different ROS control diverse aspects of cell behaviour from signalling to ...death, and deregulation of ROS production and ROS limitation pathways are common features of cancer cells. ROS also function to modulate the tumour environment, affecting the various stromal cells that provide metabolic support, a blood supply and immune responses to the tumour. Although it is clear that ROS play important roles during tumorigenesis, it has been difficult to reliably predict the effect of ROS modulating therapies. We now understand that the responses to ROS are highly complex and dependent on multiple factors, including the types, levels, localization and persistence of ROS, as well as the origin, environment and stage of the tumours themselves. This increasing understanding of the complexity of ROS in malignancies will be key to unlocking the potential of ROS-targeting therapies for cancer treatment.
The concept that dietary changes could improve the response to cancer therapy is extremely attractive to many patients, who are highly motivated to take control of at least some aspect of their ...treatment. Growing insight into cancer metabolism is highlighting the importance of nutrient supply to tumor development and therapeutic response. Cancers show diverse metabolic requirements, influenced by factors such as tissue of origin, microenvironment, and genetics. Dietary modulation will therefore need to be matched to the specific characteristics of both cancers and treatment, a precision approach requiring a detailed understanding of the mechanisms that determine the metabolic vulnerabilities of each cancer.
The concept that dietary changes could improve the response to cancer therapy is extremely attractive to many patients, who are highly motivated to take control of at least some aspect of their treatment. Growing insight into cancer metabolism is highlighting the importance of nutrient supply to tumor development and therapeutic response. Cancers show diverse metabolic requirements, influenced by factors such as tissue of origin, microenvironment, and genetics. Dietary modulation will therefore need to be matched to the specific characteristics of both cancers and treatment, a precision approach requiring a detailed understanding of the mechanisms that determine the metabolic vulnerabilities of each cancer.
p53, cancer and the immune response Blagih, Julianna; Buck, Michael D; Vousden, Karen H
Journal of cell science,
03/2020, Letnik:
133, Številka:
5
Journal Article
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The importance of cancer-cell-autonomous functions of the tumour suppressor p53 (encoded by
) has been established in many studies, but it is now clear that the p53 status of the cancer cell also has ...a profound impact on the immune response. Loss or mutation of p53 in cancers can affect the recruitment and activity of myeloid and T cells, allowing immune evasion and promoting cancer progression. p53 can also function in immune cells, resulting in various outcomes that can impede or support tumour development. Understanding the role of p53 in tumour and immune cells will help in the development of therapeutic approaches that can harness the differential p53 status of cancers compared with most normal tissue.
Crosstalk between cellular metabolism and the epigenome regulates epigenetic and metabolic homeostasis and normal cell behavior. Changes in cancer cell metabolism can directly impact epigenetic ...regulation and promote transformation. Here we analyzed the contribution of methionine and serine metabolism to methylation of DNA and RNA. Serine can contribute to this pathway by providing one-carbon units to regenerate methionine from homocysteine. While we observed this contribution under methionine-depleted conditions, unexpectedly, we found that serine supported the methionine cycle in the presence and absence of methionine through de novo ATP synthesis. Serine starvation increased the methionine/S-adenosyl methionine ratio, decreasing the transfer of methyl groups to DNA and RNA. While serine starvation dramatically decreased ATP levels, this was accompanied by lower AMP and did not activate AMPK. This work highlights the difference between ATP turnover and new ATP synthesis and defines a vital function of nucleotide synthesis beyond making nucleic acids.
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•Serine supports the methionine cycle through de novo ATP synthesis•De novo ATP-synthesis is an important source of ATP in cancer cells•Methionine fed colorectal cancer cells do not detectably re-methylate homocysteine•A method to track methyl units from amino acids onto DNA and RNA is described
The methionine cycle generates S-adenosyl methionine (SAM), the primary cellular methyl donor. Serine may provide one-carbon units to regenerate methionine from homocysteine. Maddocks et al. show that in colorectal cancer cells serine also maintains the methionine cycle through de novo ATP synthesis, which supports the conversion of methionine to SAM.
The function of p53 as a tumour suppressor has been attributed to its ability to promote cell death or permanently inhibit cell proliferation. However, in recent years, it has become clear that p53 ...can also contribute to cell survival. p53 regulates various metabolic pathways, helping to balance glycolysis and oxidative phosphorylation, limiting the production of reactive oxygen species, and contributing to the ability of cells to adapt to and survive mild metabolic stresses. Although these activities may be integrated into the tumour suppressive functions of p53, deregulation of some elements of the p53-induced response might also provide tumours with a survival advantage.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
9.
Control of metabolism by p53 – Cancer and beyond Labuschagne, Christiaan F.; Zani, Fabio; Vousden, Karen H.
Biochimica et biophysica acta. Reviews on cancer,
August 2018, 2018-08-00, 20180801, Letnik:
1870, Številka:
1
Journal Article
Recenzirano
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p53 is an important tumour suppressor gene, with loss of p53 contributing to the development of most human cancers. However, the activation of p53 in response to stress signals underpins a role for ...p53 in diverse aspects of health and disease. Activities of p53 that regulate metabolism can play a role in maintaining homeostasis and protecting cells from damage – so preventing disease development. By contrast, either loss or over-activation of p53 can contribute to numerous metabolic pathologies, including aging, obesity and diabetes.
The TIGAR protein has antioxidant activity that supports intestinal tissue repair and adenoma development. Using a pancreatic ductal adenocarcinoma (PDAC) model, we show that reactive oxygen species ...(ROS) regulation by TIGAR supports premalignant tumor initiation while restricting metastasis. Increased ROS in PDAC cells drives a phenotypic switch that increases migration, invasion, and metastatic capacity. This switch is dependent on increased activation of MAPK signaling and can be reverted by antioxidant treatment. In mouse and human, TIGAR expression is modulated during PDAC development, with higher TIGAR levels in premalignant lesions and lower TIGAR levels in metastasizing tumors. Our study indicates that temporal, dynamic control of ROS underpins full malignant progression and helps to rationalize conflicting reports of pro- and anti-tumor effects of antioxidant treatment.
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•ROS regulation by TIGAR supports premalignant pancreas tumor development•Increased ROS following TIGAR or Nrf2 loss enhance metastasis•ROS reduce DUSP6 expression to activate ERK and increase invasion and migration•TIGAR and ROS levels are dynamically regulated throughout tumor progression
Cheung et al. show that TIGAR expression is dynamically regulated during the development of pancreatic ductal adenocarcinoma, resulting in lower levels of ROS to promote tumor initiation in the premalignant condition and higher levels of ROS that enable metastatic progression.
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