Ubiquitination and deubiquitination are reversible processes that modify the characteristics of target proteins, including stability, intracellular localization, and enzymatic activity. ...Ubiquitin-specific proteases (USPs) constitute the largest deubiquitinating enzyme family. To date, accumulating evidence indicates that several USPs positively and negatively affect metabolic diseases. USP22 in pancreatic β-cells, USP2 in adipose tissue macrophages, USP9X, 20, and 33 in myocytes, USP4, 7, 10, and 18 in hepatocytes, and USP2 in hypothalamus improve hyperglycemia, whereas USP19 in adipocytes, USP21 in myocytes, and USP2, 14, and 20 in hepatocytes promote hyperglycemia. In contrast, USP1, 5, 9X, 14, 15, 22, 36, and 48 modulate the progression of diabetic nephropathy, neuropathy, and/or retinopathy. USP4, 10, and 18 in hepatocytes ameliorates non-alcoholic fatty liver disease (NAFLD), while hepatic USP2, 11, 14, 19, and 20 exacerbate it. The roles of USP7 and 22 in hepatic disorders are controversial. USP9X, 14, 17, and 20 in vascular cells are postulated to be determinants of atherosclerosis. Moreover, mutations in the
and
loci in pituitary tumors cause Cushing syndrome. This review summarizes the current knowledge about the modulatory roles of USPs in energy metabolic disorders.
NRF2 addiction in cancer cells Kitamura, Hiroshi; Motohashi, Hozumi
Cancer science,
April 2018, Letnik:
109, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The Kelch‐like ECH‐associated protein 1/nuclear factor erythroid‐derived 2‐like 2 (KEAP1‐NRF2) system is a pivotal defense mechanism against oxidative and electrophilic stress. Although transient ...NRF2 activation in response to stress is beneficial for health, persistent NRF2 activation in cancer cells has deleterious effects on cancer‐bearing hosts by conferring therapeutic resistance and aggressive tumorigenic activity on cancer cells. Because NRF2 increases the antioxidant and detoxification capability of cancer cells, persistently high levels of NRF2 activity enhance therapeutic resistance of cancer cells. NRF2 also drives metabolic reprogramming to establish cellular metabolic processes that are advantageous for cell proliferation in cooperation with other oncogenic pathways. As a result of these advantages, cancer cells with persistent activation of NRF2 often develop “NRF2 addiction” and show malignant phenotypes leading to poor prognoses in cancer patients. Inhibition of NRF2 is a promising therapeutic approach for NRF2‐addicted cancers and NRF2 inhibitors are being actively developed. However, giving systemic NRF2 inhibitors might have undesirable effects on cancer‐bearing hosts, considering the central roles of NRF2 in cytoprotection. To avoid these side‐effects, new therapeutic targets besides NRF2 for NRF2‐addicted cancers have been actively explored. This review introduces recent studies describing the development and characterization of NRF2‐addicted cancers, as well as their potential therapeutic targets. Expected advances in diagnostic and therapeutic interventions for NRF2‐addicted cancers are also discussed.
The KEAP1‐NRF2 system is a pivotal defense mechanism against oxidative and electrophilic stress. Cancer cells with persistent activation of NRF2 often develop “NRF2 addiction” and show malignant phenotypes leading to poor prognoses in cancer patients. This review introduces recent studies describing the development and characterization of NRF2‐addicted cancers, as well as their potential therapeutic targets.
There is growing evidence of the presence of cancer stem cells in urothelial carcinoma. Cancer stem cells have the ability to self‐renew and to differentiate into all cell types of the original ...heterogeneous tumor. A panel of diverse cancer stem cell markers might be suitable for simulation studies of urothelial cancer stem cells and for the development of optimized treatment protocols. The present review focuses on the advances in recognizing the markers of urothelial cancer stem cells and possible therapeutic targets. The commonly reported markers and pathways that were evaluated include CD44, CD133, ALDH1, SOX2 & SOX4, BMI1, EZH1, PD‐L1, MAGE‐A3, COX2/PGE2/STAT3, AR, and autophagy. Studies on the epithelial–mesenchymal transition‐related pathways (Shh, Wnt/β‐catenin, Notch, PI3K/Akt, TGF‐β, miRNA) are also reviewed. Most of these markers were recognized through the expression patterns of cancer stem cell‐rich side populations. Their regulative role in the development and differentiation of urothelial cancer stem cells was confirmed in vitro by functional analyses (e.g. cell migration, colony formation, sphere formation), and in vivo in xenograft experiments. Although a small number of these pathways are targeted by currently available drugs or drugs that are the currently being tested in clinical trials, a clear treatment approach has not been developed for most pathways. A greater understanding of the mechanisms that control the proliferation and differentiation of cancer stem cells is expected to lead to improvements in targeted therapy.
Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and ...Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally prevents p53 signaling. On the other hand, USP2 functions as a key component of the CLOCK/BMAL1 complex and participates in rhythmic gene expression in the suprachiasmatic nucleus and liver. USP2 variants influence energy metabolism by controlling hepatic gluconeogenesis, hepatic cholesterol uptake, adipose tissue inflammation, and subsequent systemic insulin sensitivity. USP2 also has the potential to promote surface expression of ion channels in renal and intestinal epithelial cells. In addition to modifying the production of cytokines in immune cells, USP2 also modulates the signaling molecules that are involved in cytokine signaling in the target cells.
knockout mice exhibit changes in locomotion and male fertility, which suggest roles for USP2 in the central nervous system and male genital tract, respectively. In this review, we summarize the cellular events with USP2 contributions and list the signaling molecules that are upstream or downstream of USP2. Additionally, we describe phenotypic differences found in the in vitro and in vivo experimental models.
Abstract Fenestranes, in which four rings share one carbon atom, have garnered much attention because of their flattened quaternary carbon centers. In addition, the rigid and nonplanar structures of ...heteroatom-containing fenestranes are attractive scaffolds for pharmaceutical applications. We report one-step syntheses of diaza-dioxa-fenestranes via the sequential (3 + 2) cycloadditions. Our synthesis employs readily synthesizable, nonbranched acyclic allenyl precursors that facilitate sequential cycloaddition reactions. We report the synthesis of 22 heteroatom-containing and differently substituted fenestranes with rings of varying sizes. The prepared diaza-dioxa-fenestranes are subjected to X-ray crystallography and DFT calculations, which suggest that replacing the carbon atoms at the non-bridgehead positions in the fenestrane skeleton with nitrogen and oxygen atoms results in a slight flattening of the quaternary carbon center. Moreover, one of our synthesized c , c -5.5.5.5fenestranes containing two isoxazoline rings possesses the flattest quaternary carbon center among previously synthesized heteroatom-containing fenestrane versions.
The Cre-loxP system is widely used to investigate the cell-type specific roles of genes of interest. Cre-driver mice are required for cell-type specific knockout during the Cre-loxP reaction. To ...maintain Cre-driver mouse strains, Polymerase chain reaction (PCR)-oriented genotyping targeting the Cre gene cassette is usually conducted. In this study, we instead applied a colorimetric loop-mediated isothermal amplification (LAMP) method for Cre-genotyping. Among four sets of primers designed by the in silico program, one set effectively amplified the Cre cassette of three Cre-driver strains, but not of C57BL/6 mice. This LAMP-oriented method reduces assay time by less than half compared to the PCR-based method, and can be carried out using a conventional isothermal incubator. Applying this LAMP method may accelerate genotyping of Cre-driver mice.
The transcription factor Nrf2 activates transcription of cytoprotective genes during oxidative and electrophilic insults. Nrf2 activity is regulated by Keap1 in a stress-dependent manner in normal ...cells, and somatic loss-of-function mutations of Keap1 are known to induce constitutive Nrf2 activation, especially in lung adenocarcinomas, conferring survival and proliferative benefits to tumors. Therefore, several therapeutic strategies that aim to inhibit Nrf2 in tumors have been developed for the treatment of Nrf2-activated cancers. Here we addressed whether targeting Nrf2 activation in the microenvironment can suppress the progression of Nrf2-activated tumors. We combined two types of Keap1-flox mice expressing variable levels of Keap1 with a Kras-driven adenocarcinoma model to generate Keap1-deficient lung tumors surrounded by normal or Keap1-knockdown host cells. In this model system, activation of Nrf2 in the microenvironment prolonged the survival of Nrf2-activated tumor-bearing mice. The Nrf2-activated microenvironment suppressed tumor burden; in particular, preinvasive lesion formation was significantly suppressed. Notably, loss of Nrf2 in bone marrow-derived cells in Nrf2-activated host cells appeared to counteract the suppression of Nrf2-activated cancer progression. Thus, these results demonstrate that microenvironmental Nrf2 activation suppresses the progression of malignant Nrf2-activated tumors and that Nrf2 activation in immune cells at least partially contributes to these suppressive effects. SIGNIFICANCE: This study clarifies the importance of Nrf2 activation in the tumor microenvironment and in the host for the suppression of malignant Nrf2-activated cancers and proposes new cancer therapies utilizing inducers of Nrf2.
Objectives
Despite just a 4‐year interval from the last version (2015) of the Clinical Practice Guidelines for Bladder Cancer, several dramatic paradigm shifts have occurred in the latest clinical ...practice regarding both the diagnosis and treatment of bladder cancer. Herein, we updated the 2019 version of the Clinical Practice Guidelines for Bladder Cancer under the instruction of the Japanese Urological Association.
Methods
We previously reported in a revision working position paper for Clinical Practice Guidelines for Bladder Cancer 2019 edition and described the methods of revision detail.
Results
The major points of change in the 2019 version are presented and explanations are given as follows: (i) introduction of the new reference assessment system; (ii) modification of the risk classification for non‐muscle‐invasive bladder cancer; (iii) addition of clinical questions for the new tumor‐visible techniques in non‐muscle‐invasive bladder cancer; (iv) inclusion of minimally invasive surgeries for muscle‐invasive bladder cancer and immune checkpoint inhibitors for locally advanced/metastatic muscle‐invasive bladder cancer; (v) overview chapter of the histological variant of urothelial cancer and rare cancers of the bladder; and (vi) recommendation of follow up in non‐muscle‐invasive bladder cancer and muscle‐invasive bladder cancer.
Conclusions
Guidelines should be updated based on the current evidence and updates carried out without delay. The hope is that this guidelines will be assessed by many urologists and will be the cornerstone for the next revision.
Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to ...metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in β-oxidation following suppression of transactivation by PPARα. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPARα to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPARα activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPARα activation upon fasting by promoting degradation of NCoR1 and thus regulates β-oxidation and ketone bodies production.
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