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This document is an editorial published in Frontiers in Endocrinology titled "Double-edged swords: important factors connecting metabolic disorders and cancer development -- from basic research to translational applications, volume II." The editorial discusses the intersection between metabolic dysfunction and cancer development, highlighting new challenges and opportunities in this field. It covers various topics such as drug resistance in cancer therapy, strategies to overcome resistance in hepatocellular carcinoma, the role of immunity and metabolism in liver steatosis-driven carcinogenesis, the link between metabolic factors and thyroid cancer, the role of metabolites in kidney tubulogenesis, the role of glucose metabolism in human diseases, genetic alterations in metabolic enzymes and their contribution to diseases, the potential therapeutic target of MG53 in cancer, the potential of niclosamide in cancer therapy, and the role of innate immunity and inflammation in differential susceptibilities to metabolic disorders and cancer among racial populations. The editorial concludes by emphasizing the ongoing discussion and learning about the links between metabolic functions and cancer, from basic science to translational applications. [Extracted from the article]

TP53 encodes a transcription factor that is centrally-involved in several pathways, including the control of metabolism, the stress response, DNA repair, cell cycle arrest, senescence, programmed cell death, and others. Since the discovery of TP53 as the most frequently-mutated tumor suppressor gene in cancer over four decades ago, the field has focused on uncovering target genes of this transcription factor that are essential for tumor suppression. This search has been fraught with red herrings, however. Dozens of p53 target genes were discovered that had logical roles in tumor suppression, but subsequent data showed that most were not tumor suppressive, and were dispensable for p53-mediated tumor suppression. In this review, we focus on p53 transcriptional targets in two categories: (1) canonical targets like CDKN1A (p21) and BBC3 (PUMA), which clearly play critical roles in p53-mediated cell cycle arrest/senescence and cell death, but which are not mutated in cancer, and for which knockout mice fail to develop spontaneous tumors; and (2) a smaller category of recently-described p53 target genes that are mutated in human cancer, and which appear to be critical for tumor suppression by p53. Interestingly, many of these genes encode proteins that control broad cellular pathways, like splicing and protein degradation, and several of them encode proteins that feed back to regulate p53. These include ZMAT3, GLS2, PADI4, ZBXW7, RFX7, and BTG2. The findings from these studies provide a more complex, but exciting, potential framework for understanding the role of p53 in tumor suppression. [ABSTRACT FROM AUTHOR]

Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration1. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans2,3. Its substrate, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), is not produced in metazoans, and in humans and other primates it activates cytotoxic Vγ9Vδ2 T cells at extremely low concentrations4–6. Here we describe a class of IspH inhibitors and refine their potency to nanomolar levels through structure-guided analogue design. After modification of these compounds into prodrugs for delivery into bacteria, we show that they kill clinical isolates of several multidrug-resistant bacteria—including those from the genera Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacterium and Bacillus—yet are relatively non-toxic to mammalian cells. Proteomic analysis reveals that bacteria treated with these prodrugs resemble those after conditional IspH knockdown. Notably, these prodrugs also induce the expansion and activation of human Vγ9Vδ2 T cells in a humanized mouse model of bacterial infection. The prodrugs we describe here synergize the direct killing of bacteria with a simultaneous rapid immune response by cytotoxic γδ T cells, which may limit the increase of antibiotic-resistant bacterial populations. A class of compounds with a dual mechanism of action—direct targeting of IspH and stimulation of cytotoxic γδ T cells to enhance pathogen clearance—are active against multidrug-resistant bacteria. [ABSTRACT FROM AUTHOR]

The p53 tumor suppressor protein is a transcription factor and master stress response mediator, and it is subject to reduction-oxidation (redox)-dependent regulation. The P47S variant of TP53, which exists primarily in African-descent populations, associates with an elevated abundance of low molecular weight (LMW) thiols, including glutathione (GSH) and coenzyme A (CoA). Here we show that S47 and P47 cells exhibit distinct metabolic profiles, controlled by their different redox states and expression of Activating Transcription Factor-4 (ATF4). We find that S47 cells exhibit decreased catabolic glycolysis but increased use of the pentose phosphate pathway (PPP), and an enhanced abundance of the antioxidant, NADPH. We identify ATF4 as differentially expressed in P47 and S47 cells and show that ATF4 can reverse the redox status and rescue metabolism of S47 cells, as well as increase sensitivity to ferroptosis. This adaptive metabolic switch is rapid, reversible, and accompanied by thiol-mediated changes in the structures and activities of key glycolytic signaling pathway proteins, including GAPDH and G6PD. The results presented here unveil the important functional interplay among pathways regulating thiol-redox status, metabolic adaptation, and cellular responses to oxidative stress. [ABSTRACT FROM AUTHOR]

The TP53 gene is well known to be the most frequently mutated gene in human cancer. In addition to mutations, there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene, as well as SNPs in MDM2, the negative regulator of p53. Several of these SNPs are known to alter p53 pathway function. This makes p53 rather unique among cancer-critical genes, e.g. the coding regions of other cancer-critical genes like Ha-Ras , RB , and PI3KCA do not have non-synonymous coding region SNPs that alter their function in cancer. The next frontier in p53 biology will consist of probing which of these coding region SNPs are moderately or strongly pathogenic and whether they influence cancer risk and the efficacy of cancer therapy. The challenge after that will consist of determining whether we can tailor chemotherapy to correct the defects for each of these variants. Here we review the SNPs in TP53 and MDM2 that show the most significant impact on cancer and other diseases. We also propose avenues for how this information can be used to better inform personalized medicine approaches to cancer and other diseases. [ABSTRACT FROM AUTHOR]

A population-restricted single-nucleotide coding region polymorphism (SNP) at codon 47 exists in the human TP53 gene (P47S, hereafter P47 and S47). In studies aimed at identifying functional differences between these variants, we found that the Africanspecific S47 variant associates with an impaired response to agents that induce the oxidative stress-dependent, nonapoptotic cell death process of ferroptosis. This phenotype is manifested as a greater resistance to glutamate-induced cytotoxicity in cultured cells as well as increased carbon tetrachloride-mediated liver damage in a mouse model. The differential ferroptotic responses associate with intracellular antioxidant differences between P47 and S47 cells, including elevated abundance of the low molecular weight thiols coenzyme A (CoA) and glutathione in S47 cells. Importantly, the disparate ferroptosis phenotypes related to the P47S polymorphism are reversible. Exogenous administration of CoA provides protection against ferroptosis in cultured mouse and human cells, as well as in a mouse model. The combined data support a positive role for p53 in ferroptosis and identify CoA as a regulator of this cell death process. Together, these findings provide mechanistic insight linking redox regulation of p53 to small molecule antioxidants and stress signaling pathways. They also identify potential therapeutic approaches to redox-related pathologies. [ABSTRACT FROM AUTHOR]

Approximately half of all human cancers contain mutations in the TP53 tumor suppressor. In addition to mutations, there are single nucleotide polymorphisms (SNPs) in TP53 that can dampen p53 function, and can increase cancer risk and decrease the efficacy of cancer therapy. Approximately 6% of Africans and 1% of African-Americans express a p53 allele with a serine instead of proline at position 47 (Pro47Ser, or S47). The S47 variant is associated with increased breast cancer risk in pre-menopausal African Americans, and in a mouse model for the S47 variant, mice are predisposed to spontaneous cancers. We recently showed that the S47 variant is impaired for p53-mediated apoptosis in response to radiation and some genotoxic agents, particularly cisplatin. Here we identify the mechanism for impaired apoptosis of S47 in response to cisplatin. We show that following cisplatin treatment, the S47 variant shows normal stabilization and serine 15 phosphorylation, but reduced ability to bind to the peptidyl prolyl isomerase PIN1, which controls the mitochondrial localization of p53. This is accompanied by impaired mitochondrial localization of S47, along with decreased induction of cleaved caspase-3. Interestingly, we show that this defect occurs only for cisplatin and not for camptothecin. These findings show that normal tissues may respond differently to genotoxic stress depending upon this TP53 genotype. These data suggest that toxicity to cisplatin may be decreased in S47 individuals, and that this compound may be a superior treatment option for these individuals. [ABSTRACT FROM AUTHOR]

The tumor protein P53 (TP53, or p53) has complex and at times seemingly contradictory roles in the regulation of metabolism and ferroptosis sensitivity. We find that the actions of p53 influence the redox state, which can trigger changes in redox-sensitive proteins, thereby modifying metabolic processes and response to ferroptosis. [ABSTRACT FROM AUTHOR]

The p53 tumor suppressor continues to be distinguished as the most frequently mutated gene in human cancer. It is widely believed that the ability of p53 to induce senescence and programmed cell death underlies the tumor suppressor functions of p53. However, p53 has a number of other functions that recent data strongly implicate in tumor suppression, particularly with regard to the control of metabolism and ferroptosis (iron- and lipid-peroxide-mediated cell death) by p53. As reviewed here, the roles of p53 in the control of metabolism and ferroptosis are complex. Wild-type (WT) p53 negatively regulates lipid synthesis and glycolysis in normal and tumor cells, and positively regulates oxidative phosphorylation and lipid catabolism. Mutant p53 in tumor cells does the converse, positively regulating lipid synthesis and glycolysis. The role of p53 in ferroptosis is even more complex: in normal tissues, WT p53 appears to positively regulate ferroptosis, and this pathway appears to play a role in the ability of basal, unstressed p53 to suppress tumor initiation and development. In tumors, other regulators of ferroptosis supersede p53's role, and WT p53 appears to play a limited role; instead, mutant p53 sensitizes tumor cells to ferroptosis. By clearly elucidating the roles of WT and mutant p53 in metabolism and ferroptosis, and establishing these roles in tumor suppression, emerging research promises to yield new therapeutic avenues for cancer and metabolic diseases. [ABSTRACT FROM AUTHOR]

Cross-presentation is a critical function of dendritic cells (DCs) required for induction of antitumor immune responses and success of cancer immunotherapy. It is established that tumor-associated DCs are defective in their ability to cross-present antigens. However, the mechanisms driving these defects are still unknown. We find that impaired crosspresentation in DCs is largely associated with defect in trafficking of peptide-MHC class I (pMHC) complexes to the cell surface. DCs in tumor-bearing hosts accumulate lipid bodies (LB) containing electrophilic oxidatively truncated (ox-tr) lipids. These ox-tr-LB, but not LB present in control DCs, covalently bind to chaperone heat shock protein 70. This interaction prevents the translocation of pMHC to cell surface by causing the accumulation of pMHC inside late endosomes/lysosomes. As a result, tumor-associated DCs are no longer able to stimulate adequate CD8 T cells responses. In conclusion, this study demonstrates a mechanism regulating cross-presentation in cancer and suggests potential therapeutic avenues. [ABSTRACT FROM AUTHOR]

TheTP53gene is distinguished as the most frequently mutated gene in cancer. Unlike most cancer-relevant genes, theTP53gene is also distinguished by the existence of coding region polymorphisms that alter p53 sequence, and in some cases, also alter p53 function. A common coding region variant at amino acid 72 of p53 encodes either proline (P72) or arginine (R72). P72 is the ancestral variant and is most common in populations near the equator. The frequency of the R72 variant increases in a linear manner with latitude. To date, why the R72 variant arose in humans and was possibly selected for has remained unclear. Here-in we show that this single nucleotide polymorphism (SNP) influences the phosphorylation of p53 and the transactivation of the key p53 targetCDKN1A(p21) specifically in response to nutrient deprivation, but not in response to conventional cytotoxic agents. Following activation of the kinase AMPK, R72 cells show increased phosphorylation on serine-15 and increased transactivation of the cyclin-dependent kinase inhibitorCDKN1A(p21) and the metabolic response genesPPARGC1B(PGC-1β) andPRKAB2(AMPK-β2). This is accompanied by increased growth arrest and decreased apoptosis in R72 cells compared with P72 cells. The combined data fit best with the hypothesis that the R72 polymorphism confers increased cell survival in response to nutrient deprivation. This differential response to nutrient deprivation may explain part of selection for this SNP at northern latitudes, where nutrient deprivation might have been more frequent. [ABSTRACT FROM PUBLISHER]

In the context of tumor suppression, p53 is an undisputedly critical protein. Functioning primarily as a transcription factor, p53 helps fend off the initiation and progression of tumors by inducing cell cycle arrest, senescence or programmed cell death (apoptosis) in cells at the earliest stages of precancerous development. Compelling evidence, however, suggests that p53 is involved in other aspects of human physiology, including metabolism. Indeed, recent studies suggest that p53 plays a significant role in the development of metabolic diseases, including diabetes, and further that p53's role in metabolism may also be consequential to tumor suppression. Here, we present a review of the literature on the role of p53 in metabolism, diabetes, pancreatic function, glucose homeostasis and insulin resistance. Additionally, we discuss the emerging role of genetic variation in the p53 pathway (single-nucleotide polymorphisms) on the impact of p53 in metabolic disease and diabetes. A better understanding of the relationship between p53, metabolism and diabetes may one day better inform the existing and prospective therapeutic strategies to combat this rapidly growing epidemic. [ABSTRACT FROM AUTHOR]

Highlights from the article: Our understanding of cancer development has been marked by milestone discoveries in genetics, including the identification and cloning of oncogenes and tumor suppressor genes ([1]). Compared to the roles of cancer-associated genes in metabolic disorders, our understanding of how metabolic-disease genes regulate tumorigenesis is only now emerging. They also discuss the recently-identified associations between dNTP homeostasis and metabolic diseases, and the potential novel therapeutic strategies targeting these interconnections for cancer and metabolic disorders.

Summary p53 is well known for its tumor suppressor role, but this protein also has a poorly understood role in the regulation of metabolism. Human studies have implicated a common polymorphism at codon 72 of p53 in diabetic and pre-diabetic phenotypes. To understand this role, we utilized a humanized mouse model of the p53 codon 72 variants and monitored these mice following challenge with a high-fat diet (HFD). Mice with the arginine 72 (R72) variant of p53 developed more-severe obesity and glucose intolerance on a HFD, compared to mice with the proline 72 variant (P72). R72 mice developed insulin resistance, islet hypertrophy, increased infiltration of immune cells, and fatty liver disease. Gene expression analyses and studies with small-molecule inhibitors indicate that the p53 target genes Tnf and Npc1l1 underlie this phenotype. These results shed light on the role of p53 in obesity, metabolism, and inflammation. [ABSTRACT FROM AUTHOR]

The HSP70 family of molecular chaperones function to maintain protein quality control and homeostasis. The major stress-induced form, HSP70 (also called HSP72 or HSPA1A) is considered an important anti-cancer drug target because it is constitutively overexpressed in a number of human cancers and promotes cancer cell survival. All HSP70 family members contain two functional domains: an N-terminal nucleotide binding domain (NBD) and a C-terminal protein substrate-binding domain (SBD); the latter is subdivided into SBDα and SBDβ subdomains. The NBD and SBD structures of the bacterial ortholog, DnaK, have been characterized, but only the isolated NBD and SBDα segments of eukaryotic HSP70 proteins have been determined. Here we report the crystal structure of the substrate-bound human HSP70-SBD to 2 angstrom resolution. The overall fold of this SBD is similar to the corresponding domain in the substrate-bound DnaK structures, confirming a similar overall architecture of the orthologous bacterial and human HSP70 proteins. However, conformational differences are observed in the peptide-HSP70-SBD complex, particularly in the loop Lα, β that bridges SBDα to SBDβ, and the loop LL,1 that connects the SBD and NBD. The interaction between the SBDα and SBDβ subdomains and the mode of substrate recognition is also different between DnaK and HSP70. This suggests that differences may exist in how different HSP70 proteins recognize their respective substrates. The high-resolution structure of the substrate-bound-HSP70-SBD complex provides a molecular platform for the rational design of small molecule compounds that preferentially target this C-terminal domain, in order to modulate human HSP70 function. [ABSTRACT FROM AUTHOR]