Результаты поиска

p53 Deletion or Hotspot Mutations Enhance mTORC1 Activity by Altering Lysosomal Dynamics of TSC2 and Rheb.

UNLABELLED: The activity of mammalian target of rapamycin complex 1 (mTORC1) is frequently enhanced in carcinomas, an effect thought to contribute to the malignant phenotype. Here, it is demonstrated that either deletion or mutation of TP53 in colon or lung carcinoma cells substantially enhances mTORC1 kinase activity by an effect downstream of and independent of AMPK. Mechanistically, it was determined that loss or mutation of p53 decreased expression of TSC2 and Sestrin2 (SESN2). Complementation of p53 null cells with TSC2 or Sestrin2 reduced mTORC1 activity to levels found in p53 wild-type

HOXA13 contributes to gastric carcinogenesis through DHRS2 interacting with MDM2 and confers 5-FU resistance by a p53-dependent pathway.

5-FU-based chemotherapy is recently most recommended as the first-line treatment for gastric cancer (GC). However, 5-FU resistance is common for many postoperative GC patients. Homeobox A13 (HOXA13) is a member of homeobox genes highly expressed in many human tumors. Its potential roles and mechanisms of resistance to 5-FU in GC are poorly understood. In this study, we discovered that HOXA13 played an oncogenic role in vivo and in vitro. The patients with HOXA13 overexpression were closely related with poor prognosis and more prone to be resistant to 5-FU. Moreover, dehydrogenase/reductase 2 (

MutLα heterodimers modify the molecular phenotype of Friedreich ataxia.

BACKGROUND: Friedreich ataxia (FRDA), the most common autosomal recessive ataxia disorder, is caused by a dynamic GAA repeat expansion mutation within intron 1 of FXN gene, resulting in down-regulation of frataxin expression. Studies of cell and mouse models have revealed a role for the mismatch repair (MMR) MutS-heterodimer complexes and the PMS2 component of the MutLα complex in the dynamics of intergenerational and somatic GAA repeat expansions: MSH2, MSH3 and MSH6 promote GAA repeat expansions, while PMS2 inhibits GAA repeat expansions. METHODOLOGY/PRINCIPAL FINDINGS: To determine the pot

Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer.

Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity, but its expression is increased in some cancers via stabilization with HSP90-associated chaperones. Here, we show that MIF stabilization is tumor-specific in an acute colitis-associated colorectal cancer (CRC) mouse model, leading to tumor-specific functions and selective therapeutic vulnerabilities. Therefore, we demonstrate that a Mif deletion reduced CRC tumor growth. Further, we define a dual role for MIF in CRC tumor progression. Mif deletion protects mice from inflammation-associated tumor initiatio

Nimbolide sensitizes human colon cancer cells to TRAIL through reactive oxygen species- and ERK-dependent up-regulation of death receptors, p53, and Bax.

TNF-related apoptosis-inducing ligand (TRAIL) shows promise as a cancer treatment, but acquired tumor resistance to TRAIL is a roadblock. Here we investigated whether nimbolide, a limonoid, could sensitize human colon cancer cells to TRAIL. As indicated by assays that measure esterase activity, sub-G(1) fractions, mitochondrial activity, and activation of caspases, nimbolide potentiated the effect of TRAIL. This limonoid also enhanced expression of death receptors (DRs) DR5 and DR4 in cancer cells. Gene silencing of the receptors reduced the effect of limonoid on TRAIL-induced apoptosis. Using

E2F1-dependent pathways are involved in amonafide analogue 7-d-induced DNA damage, G2/M arrest, and apoptosis in p53-deficient K562 cells.

The E2F1 gene well known is its pivotal role in regulating the entry from G1 to S phase, while the salvage antitumoral pathway which implicates it, especially in the absence of p53, is not fully characterized. We therefore attempted to identify the up- and down-stream events involved in the activation of the E2F1-dependent pro-apoptotic pathway. For this purpose, a amonafide analogue, 7-d (2-(3-(2-(Dimethylamino)ethylamino)propyl)-6-(dodecylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione) was screened, which exhibited high antitumor activity against p53-deficient human Chronic Myelogenous Leukem

The concerted roles of FANCM and Rad52 in the protection of common fragile sites.

Common fragile sites (CFSs) are prone to chromosomal breakage and are hotspots for chromosomal rearrangements in cancer cells. We uncovered a novel function of Fanconi anemia (FA) protein FANCM in the protection of CFSs that is independent of the FA core complex and the FANCI-FANCD2 complex. FANCM, along with its binding partners FAAP24 and MHF1/2, is recruited to CFS-derived structure-prone AT-rich sequences, where it suppresses DNA double-strand break (DSB) formation and mitotic recombination in a manner dependent on FANCM translocase activity. Interestingly, we also identified an indispensa

Structures of KIX domain of CBP in complex with two FOXO3a transactivation domains reveal promiscuity and plasticity in coactivator recruitment.

Forkhead box class O 3a (FOXO3a) is a transcription factor and tumor suppressor linked to longevity that determines cell fate through activating transcription of cell differentiation, survival, and apoptotic genes. Recruitment of the coactivator CBP/p300 is a crucial step in transcription, and we revealed that in addition to conserved region 3 (CR3) of FOXO3a, the C-terminal segment of CR2 (CR2C) binds CBP/p300 and contributes to transcriptional activity. CR2C and CR3 of FOXO3a interact with the KIX domain of CBP/p300 at both "MLL" and "c-Myb" binding sites simultaneously. A FOXO3a CR2C-CR3 pe

IκB kinase α phosphorylation of TRAF4 downregulates innate immune signaling.

Despite their homology, IκB kinase α (IKKα) and IKKβ have divergent roles in NF-κB signaling. IKKβ strongly activates NF-κB while IKKα can downregulate NF-κB under certain circumstances. Given this, identifying independent substrates for these kinases could help delineate their divergent roles. Peptide substrate array technology followed by bioinformatic screening identified TRAF4 as a substrate for IKKα. Like IKKα, TRAF4 is atypical within its family because it is the only TRAF family member to negatively regulate innate immune signaling. IKKα's phosphorylation of serine-426 on TRAF4 was requ

Modulating cancer cell survival by targeting intracellular cholesterol transport.

BACKGROUND: Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential approach involves disruption of intracellular cholesterol transport, which occurs in Niemann-Pick disease as a result of acid sphingomyelinase (ASM) deficiency. Hence, a class of lysosomotropic compounds that were identified as functional ASM inhibitors (FIASMAs) might exhibit chemotherapeutic activity by disrupting cancer cell cholesterol homoeostasis. METHODS: Here, the chemotherapeutic utility of ASM inhibition wa

Homocysteine promotes human endothelial cell dysfunction via site-specific epigenetic regulation of p66shc.

AIMS: Hyperhomocysteinaemia is an independent risk factor for atherosclerotic vascular disease and is associated with vascular endothelial dysfunction. Homocysteine modulates cellular methylation reactions. P66shc is a protein that promotes oxidative stress whose expression is governed by promoter methylation. We asked if homocysteine induces endothelial p66shc expression via hypomethylation of CpG dinucleotides in the p66shc promoter, and whether p66shc mediates homocysteine-stimulated endothelial cell dysfunction. METHODS AND RESULTS: Homocysteine stimulates p66shc transcription in human en

Furin-, ADAM 10-, and gamma-secretase-mediated cleavage of a receptor tyrosine phosphatase and regulation of beta-catenin's transcriptional activity.

Several receptor protein tyrosine phosphatases (RPTPs) are cell adhesion molecules involved in homophilic interactions, suggesting that RPTP outside-in signaling is coupled to cell contact formation. However, little is known about the mechanisms by which cell density regulates RPTP function. We show that the MAM family prototype RPTPkappa is cleaved by three proteases: furin, ADAM 10, and gamma-secretase. Cell density promotes ADAM 10-mediated cleavage and shedding of RPTPkappa. This is followed by gamma-secretase-dependent intramembrane proteolysis of the remaining transmembrane part to relea

Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer.

BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and di

AMP-activated Protein Kinase (AMPK) Control of mTORC1 Is p53- and TSC2-independent in Pemetrexed-treated Carcinoma Cells.

The key sensor of energy status in mammalian cells, AMP-activated protein kinase (AMPK), can also be activated by the AMP analog aminoimidazolecarboxamide nucleoside monophosphate (ZMP) generated directly from aminoimidazolecarboxamide ribonucleoside (AICAR) or from inhibition of purine synthesis by the antifolate pemetrexed (PTX), a drug used extensively in the treatment of lung cancers. Despite this common mechanism, signaling downstream of AMPK activated by PTX or AICAR differed. AICAR-activated AMPK inhibited mTORC1 both directly by phosphorylation of the mTORC1 subunit Raptor and indirect

Advances in delivery methods of Arthrospira platensis (spirulina) for enhanced therapeutic outcomes.

Arthrospira platensis (A. platensis) aqueous extract has massive amounts of natural products that can be used as future drugs, such as C-phycocyanin, allophycocyanin, etc. This extract was chosen because of its high adaptability, which reflects its resolute genetic composition. The proactive roles of cyanobacteria, particularly in the medical field, have been discussed in this review, including the history, previous food and drug administration (FDA) reports, health benefits and the various dose-dependent therapeutic functions that A. platensis possesses, including its role in fighting against

EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences.

TP63 germ-line mutations are responsible for a group of human ectodermal dysplasia syndromes, underlining the key role of P63 in the development of ectoderm-derived tissues. Here, we report the identification of two TP63 alleles, G134V (p.Gly173Val) and insR155 (p.Thr193_Tyr194insArg), associated to ADULT and EEC syndromes, respectively. These alleles, along with previously identified G134D (p.Gly173Asp) and R204W (p.Arg243Trp), were functionally characterized in yeast, studied in a mammalian cell line and modeled based on the crystal structure of the P63 DNA-binding domain. Although the p.Arg

Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways.

BACKGROUND/AIMS: The clinical utility of 5-fluorouracil (5-FU) is limited by its nephrotoxicity. Camel milk (CM) has previously displayed beneficial effects in toxicant-induced nephropathies. The current study aimed to investigate the potential of CM to attenuate 5-FU-induced nephrotoxicity in rats. METHODS: Renal tissues were studied in terms of oxidative stress, inflammation and apoptosis. The levels of renal injury markers, inflammatory cytokines along with NOX-1, Nrf-2 and HO-1 were assessed by ELISA. The expression of MMP-2, MMP-9, NF-κBp65, p53, Bax and PCNA were detected by Immunohisto

Decreased transcription-coupled nucleotide excision repair capacity is associated with increased p53- and MLH1-independent apoptosis in response to cisplatin.

BACKGROUND: One of the most commonly used classes of anti-cancer drugs presently in clinical practice is the platinum-based drugs, including cisplatin. The efficacy of cisplatin therapy is often limited by the emergence of resistant tumours following treatment. Cisplatin resistance is multi-factorial but can be associated with increased DNA repair capacity, mutations in p53 or loss of DNA mismatch repair capacity. METHODS: RNA interference (RNAi) was used to reduce the transcription-coupled nucleotide excision repair (TC-NER) capacity of several prostate and colorectal carcinoma cell lines wi

Targeting the E2F1/Rb/HDAC1 axis with the small molecule HR488B effectively inhibits colorectal cancer growth.

Colorectal cancer (CRC), the third most common cancer worldwide, remains highly lethal as the disease only becomes symptomatic at an advanced stage. Growing evidence suggests that histone deacetylases (HDACs), a group of epigenetic enzymes overexpressed in precancerous lesions of CRC, may represent promising molecular targets for CRC treatment. Histone deacetylase inhibitors (HDACis) have gradually become powerful anti-cancer agents targeting epigenetic modulation and have been widely used in the clinical treatment of hematologic malignancies, while only few studies on the benefit of HDACis in

Совпадение в полном тексте источника
… To further determine the target specificity of HR488B, we knocked down HDAC1 to confirm whether the inhibitory effect of HR488B on HCT116 cells is affected. In the siNC group, treatment with HR488B led to a remarkable downregulation of HCT116 cell viability compared to the DMSO-treated group. … We also found that the knockdown of E2F1 blocked the HR488B-induced accumulation of ROS in HCT116 cells (Fig. S8a, b ). …

CPUY201112, a novel synthetic small-molecule compound and inhibitor of heat shock protein Hsp90, induces p53-mediated apoptosis in MCF-7 cells.

Heat-shock protein 90 (Hsp90) is highly expressed in many tumor cells and is associated with the maintenance of malignant phenotypes. Targeting Hsp90 has had therapeutic success in both solid and hematological malignancies, which has inspired more studies to identify new Hsp90 inhibitors with improved clinical efficacy. Using a fragment-based approach and subsequent structural optimization guided by medicinal chemistry principles, we identified the novel compound CPUY201112 as a potent Hsp90 inhibitor. It binds to the ATP-binding pocket of Hsp90 with a kinetic dissociation (Kd) constant of 27

Совпадение в полном тексте источника
… However, from these results we concluded that CPUY201112 induced p53-mediated apoptosis in HCT116 cells. Figure 7 CPUY201112 enhances wt -p53 signaling and kills cancer cells in a wt -p53-dependent manner. ( A ) Cell viability assay. … As a result, p53 and p21 protein was also significantly up-regulated in MCF-7 and HCT116 cells upon combined treatment compared with Nutlin-3a or CPUY201112 alone ( Fig. 8C ). In conclusion, CPUY201112 enhanced the p53 signaling pathway to promote apoptosis. …