p53 is the major tumor suppressor and the most frequently inactivated gene in cancer. p53 could be disabled either by mutations or by upstream negative regulators, including, but not limited to MDM2 ...and MDMX. p53 activity is required for the prevention as well as for the eradication of cancers. Restoration of p53 activity in mouse models leads to the suppression of established tumors of different origin. These findings provide a strong support to the anti-cancer strategy aimed for p53 reactivation. In this review, we summarize recent progress in the development of small molecules, which restore the tumor suppressor function of wild-type p53 and discuss their clinical advance. We discuss different aspects of p53-mediated response, which contribute to suppression of tumors, including non-canonical p53 activities, such as regulation of immune response. While targeting p53 inhibitors is a very promising approach, there are certain limitations and concerns that the intensive research and clinical evaluation of compounds will hopefully help to overcome.
In most countries, a government agency or collaborating organization gathers information on occupational accidents. Comparisons based on a single factor such as autonomous community, activity sector ...or others, often leads to contradictory conclusions. The use of this information for comparison is not immediate because the different characteristics considered give place to different possible comparisons. The elaboration of a single baseline for each set of characteristics is addressed. The method proposed comes from the data available in Spain but could be applied to other cases. The method consists of: (1) selecting factors-those selected are age, sex, autonomous community and activity; (2) the generation of a synthetic population based on data from a survey and general proportions by applying the Optimal Representative Sample Weighting (rsw); and (3) the prediction of the accidents ratio for each set of characteristic by using a XGBoost decision trees ensemble. The results confirm the appropriateness of the method.
Increasing evidence highlights the role of bacteria in the physiopathology of cancer. However, the underlying molecular mechanisms remains poorly understood. Several cancer-associated bacteria have ...been shown to produce toxins which interfere with the host defense against tumorigenesis. Here, we show that lipopolysaccharides from Klebsiella pneumoniae and other Enterobacteria strongly inhibit the host tumor suppressor p53 pathway through a novel mechanism of p53 regulation. We found that lipopolysaccharides destabilize TP53 mRNA through a TLR4-NF-κB-mediated inhibition of the RNA-binding factor Wig-1. Importantly, we show that K. pneumoniae disables two major tumor barriers, oncogene-induced DNA damage signaling and senescence, by impairing p53 transcriptional activity upon DNA damage and oncogenic stress. Furthermore, we found an inverse correlation between the levels of TLR4 and p53 mutation in colorectal tumors. Hence, our data suggest that the repression of p53 by Enterobacteria via TLR4 alleviates the selection pressure for p53 oncogenic mutations and shapes the genomic evolution of cancer.
The repression of repetitive elements is an important facet of p53's function as a guardian of the genome. Paradoxically, we found that p53 activated by MDM2 inhibitors induced the expression of ...endogenous retroviruses (ERV) via increased occupancy on ERV promoters and inhibition of two major ERV repressors, histone demethylase LSD1 and DNA methyltransferase DNMT1. Double-stranded RNA stress caused by ERVs triggered type I/III interferon expression and antigen processing and presentation. Pharmacologic activation of p53 in vivo unleashed the IFN program, promoted T-cell infiltration, and significantly enhanced the efficacy of checkpoint therapy in an allograft tumor model. Furthermore, the MDM2 inhibitor ALRN-6924 induced a viral mimicry pathway and tumor inflammation signature genes in patients with melanoma. Our results identify ERV expression as the central mechanism whereby p53 induction overcomes tumor immune evasion and transforms tumor microenvironment to a favorable phenotype, providing a rationale for the synergy of MDM2 inhibitors and immunotherapy.
We found that p53 activated by MDM2 inhibitors induced the expression of ERVs, in part via epigenetic factors LSD1 and DNMT1. Induction of IFN response caused by ERV derepression upon p53-targeting therapies provides a possibility to overcome resistance to immune checkpoint blockade and potentially transform "cold" tumors into "hot." This article is highlighted in the In This Issue feature, p. 2945.
The p53-family member TAp73 is known to function as a tumor suppressor and regulates genomic integrity, cellular proliferation, and apoptosis; however, its role in tumor angiogenesis is poorly ...understood. Here we demonstrate that TAp73 regulates tumor angiogenesis through repression of proangiogenic and proinflammatory cytokines. Importantly, loss of TAp73 results in highly vascularized tumors, as well as an increase in vessel permeability resulting from disruption of vascular endothelial-cadherin junctions between endothelial cells. In contrast, loss of the oncogenic p73 isoform ΔNp73 leads to reduced blood vessel formation in tumors. Furthermore, we show that up-regulated ΔNp73 levels are associated with increased angiogenesis in human breast cancer and that inhibition of TAp73 results in an accumulation of HIF-1α and up-regulation of HIF-1α target genes. Taken together, our data demonstrate that loss of TAp73 or ΔNp73 up-regulation activates the angiogenic switch that stimulates tumor growth and progression.
Abstract
Background
The estrogen receptor (ER)-positive breast cancer represents over 80% of all breast cancer cases. Even though adjuvant hormone therapy with tamoxifen (TMX) is saving lives of ...patients with ER-positive breast cancer, the acquired resistance to TMX anti-estrogen therapy is the main hurdle for successful TMX therapy. Here we address the mechanism for TMX resistance and explore the ways to eradicate TMX-resistant breast cancer in both in vitro and ex vivo experiments.
Experimental design
To identify compounds able to overcome TMX resistance, we used short-term and long-term viability assays in cancer cells in vitro and in patient samples in 3D ex vivo, analysis of gene expression profiles and cell line pharmacology database, shRNA screen, CRISPR-Cas9 genome editing, real-time PCR, immunofluorescent analysis, western blot, measurement of oxidative stress using flow cytometry, and thioredoxin reductase 1 enzymatic activity.
Results
Here, for the first time, we provide an ample evidence that a high level of the detoxifying enzyme SULT1A1 confers resistance to TMX therapy in both in vitro and ex vivo models and correlates with TMX resistance in metastatic samples in relapsed patients. Based on the data from different approaches, we identified three anticancer compounds, RITA (
R
eactivation of p53 and
I
nduction of
T
umor cell
A
poptosis), aminoflavone (AF), and oncrasin-1 (ONC-1), whose tumor cell inhibition activity is dependent on SULT1A1. We discovered thioredoxin reductase 1 (TrxR1, encoded by
TXNRD1
) as a target of bio-activated RITA, AF, and ONC-1. SULT1A1 depletion prevented the inhibition of TrxR1, induction of oxidative stress, DNA damage signaling, and apoptosis triggered by the compounds. Notably, RITA efficiently suppressed TMX-unresponsive patient-derived breast cancer cells ex vivo.
Conclusion
We have identified a mechanism of resistance to TMX via hyperactivated SULT1A1, which renders selective vulnerability to anticancer compounds RITA, AF, and ONC-1, and provide a rationale for a new combination therapy to overcome TMX resistance in breast cancer patients. Our novel findings may provide a strategy to circumvent TMX resistance and suggest that this approach could be developed further for the benefit of relapsed breast cancer patients.
Spain is one of the many countries highly affected by the COVID-19 crisis, establishing very restrictive measures with a complete lockdown for more than 3 months. This situation forced the complete ...closure of sport practice and national or international competitions, leading to a negative impact on physical and psychological health of high-performance athletes. Therefore, the objectives of this study were (a) to determine the effects of the COVID-19 health crisis on Spanish high-performance athletes in terms of sports practice, life quality, and emotional state and (b) to identify the profile with the greatest difficulties during and after the lockdown. A sample of 130 high-performance athletes aged between 18 and 34 years (67 women and 63 men) participated in this study (83.1% achieved a medal in National–International elite competitions; 86.9% were considered student-athletes). Measures included socio-demographic data through a 5-dimension
ad hoc
survey: physical activity and exercise using an adapted version from the
International Physical Activity Questionnaire (IPAQ)
; health status and limitations using an adapted version of
SF-12 Health Questionnaire
; Perceived stress
(Short-PSS)
; and Mood States (29-item
POMS
). All participants have shown a significant decrease pre–post-lockdown in both health and performance perception, especially in women, individual athletes, medalists, and student-athletes. Strong limitations of training, attention, and motivation as well as a moderate negative emotional state during lockdown were reported, in women, individual athletes, medalists, and student-athletes. Even with an improved emotional state and energy level in the post-lockdown period, moderate-to-high stress scores were reported by women and medalists. Our findings highlight the importance of paying attention to the physical and psychological health of elite athletes on three profiles: team athletes (due to social distance), student-athletes (dual-career issues), and women athletes (prevalence of implicit gender inequalities in sport).
The durability and degradation of polymers is very important for product design in terms of material choice. The degradation behavior of two biodegradable thermoplastic materials manufactured by 3D ...printing, Enviro ABS and PLA, was studied. The action of the sun and seawater was simulated to find out how they affect the properties of these materials over a period of 8 weeks. The yield strength, maximum elongation, ultimate tensile strength, and microscopy were analyzed, as well as dimensions and mass changes. These biodegradable materials were studied to conclude whether there is an environmentally friendly alternative to traditional ABS, being one of the most widely used petroleum-based plastics in industry and in fused deposition modeling (FDM) or fused filament fabrication (FFF). PLA showed a weight loss and increase in ultimate tensile stress on degradation by sunlight and a prolonged decrease in ultimate tensile stress on degradation by seawater due to humidity absorption. In contrast, Enviro ABS does not show a noticeable difference between the beginning and the end of the test, which leads to the conclusion that Enviro ABS is a good alternative to conventional ABS without forgetting the environmental effects that are currently involved in the manufacture, recycling and composting of this type of material.
The glucose-sensing enzyme glucokinase (GK) plays a key role in glucose metabolism. We report here the effects of a novel glucokinase activator, LY2121260. The activator enhanced GK activity via ...binding to the allosteric site located in the hinge region of the enzyme. LY2121260 stimulated insulin secretion in a glucose-dependent manner in pancreatic β-cells and increased glucose use in rat hepatocytes. In addition, incubation of β-cells with the GK activator resulted in increased GK protein levels, suggesting that enhanced insulin secretion on chronic treatment with a GK activator may be due to not only changed enzyme kinetics but also elevated enzyme levels. Animals treated with LY2121260 showed an improved glucose tolerance after oral glucose challenge. These results support the concept that GK activators represent a new class of compounds that increase both insulin secretion and hepatic glucose use and in doing so may prove to be effective agents for the control of blood glucose levels in patients with type 2 diabetes.
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