scholarly journals 3-HAA Metabolic Pathway Regulates HCC Growth

2021 ◽  
Author(s):  
Zhaopeng Shi ◽  
Guifang Gan ◽  
Xianfu Gao ◽  
Fuxiang Chen ◽  
Jun Mi
Keyword(s):  
Tumor Growth ◽  
Metabolic Pathway ◽  
Tumor Formation ◽  
Aryl Hydrocarbon ◽  
Mechanistic Investigation ◽  
Tryptophan Metabolites ◽  
Hydroxyanthranilic Acid ◽  
Induced Apoptosis

Abstract Background Kynurenine, a metabolite of tryptophan, promotes immune tolerance in development and tumor evasion by binding to the aryl hydrocarbon receptor (AHR). However, the kynurenine catabolic enzyme IDO1 inhibitors fail in clinical trials. Methods The LC-MS/MS and GC-MS/MS were performed to measure the concentration of tryptophan metabolites. The PCX model, PDX model, and transposon liver cancer models were used to evaluate the effects of 3-HAA, DUSP6, and YY1 on HCC tumor formation and/or tumor growth. Results 3-hydroxyanthranilic acid (3-HAA) induced HCC apoptosis and reduced xenografted tumor growth, the survival of the transposon HCC mice, and synergized with IDO1 inhibitor on HCC growth in vivo. Overexpression of 3-HAA synthesis enzyme KMO suppressed tumor formation and tumor growth by increasing endogenous 3-HAA while adding exogenous 3-HAA also inhibited tumor growth. Notably, 3-HAA was lower in tumor cells due to the downregulation of its synthetic enzyme KMO/KYNU and/or upregulation of its catalytic enzyme HAAO. The mechanistic investigation demonstrated that 3-HAA induced dual-specificity phosphatase 6 (DUSP6) transcription. DUSP6 overexpression induced apoptosis of hepatocellular carcinoma (HCC) cells and suppressed the HCC growth in vitro and in vivo. DUSP6 knockdown abolished 3-HAA-induced apoptosis and restores tumor growth. Conclusions These findings demonstrate that 3-HAA metabolic pathway regulates HCC cell growth, suggesting it is a promising therapeutic candidate for HCC.

scholarly journals Kynurenine analog 3-HAA is a ligand for transcription factor YY1

2020 ◽  
Author(s):  
Zhaopeng Shi ◽  
Guifang Gan ◽  
Xiang Xu ◽  
Jieying Zhang ◽  
Yuan Yuan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Formation ◽  
Aryl Hydrocarbon ◽  
Ido Inhibitors ◽  
Induced Apoptosis ◽  
Transcription Factor Yy1

Abstract Kynurenine, a metabolite of tryptophan, promotes immune tolerance in development and tumor evasion by binding to the aryl hydrocarbon receptor (AHR). However, the IDO inhibitors, blocking kynurenine generation, fail in stage III of clinical trials in several tumors for unknown reasons. Here, we report that 3-hydroxyanthranilic acid (3-HAA) synergizes with IDO inhibitors by dramatically increasing the suppression of IDO inhibitors on HCC xenograft growth. The content of 3-HAA, a catabolite of kynurenine, is lower in tumor cells by downregulating its synthetic enzyme KMO/KYNU and/or upregulating its catalytic enzyme HAAO. Overexpression of KMO suppresses tumor formation and tumor growth by increasing endogenous 3-HAA while adding exogenous 3-HAA also inhibits tumor growth. Moreover, we found that 3-HAA directly binds transcription factor YY1 rather than AHR and increasing the PKCζ phosphorylation of YY1 at the Thr 398 in response to 3-HAA; YY1 phosphorylation at T398 increases the YY1 binding to chromatin. 3-HAA-induced Thr398 phosphorylation of YY1 upregulates the expression of dual-specificity phosphatase 6 (DUSP6), etc. DUSP6 overexpression induces apoptosis of hepatocellular carcinoma (HCC) cells and suppresses the HCC growth in vitro and in vivo. The T398 phosphorylation of YY1 is critical for the 3-HAA-induced apoptosis in tumors. These findings demonstrate that kynurenine analog 3-HAA is a functional metabolite associating YY1 as an endogenous ligand, downregulation of 3-HAA is necessary for the rapid growth of tumor cells, suggesting its promising approach in HCC therapy.

scholarly journals MicroRNA-381 inhibits bladder cancer pathogenesis through directly controlling BMI1 and triggering the Rho/ROCK signaling pathway defect

2020 ◽  
Author(s):  
Dayin Chen ◽  
Liang Cheng ◽  
Huifeng Cao ◽  
Wensi Liu
Keyword(s):  
Bladder Cancer ◽  
Tumor Growth ◽  
Cancer Control ◽  
Tumor Formation ◽  
Luciferase Assay ◽  
Cell Behaviors ◽  
Cancer Pathogenesis ◽  
Bmi1 Expression

Abstract Background Emerging evidence has noted the important participation of microRNAs (miRNAs) in several human diseases including cancer control. This research was launched to probe the function of miR-381 in bladder cancer (BCs) progression. Methods Aberrantly expressed miRNAs in BCs tissues were analyzed using miRNA microarrays. miR-381 expression in the bladder and paired tumor tissues, and in BCs and normal cell lines was determined. The target relationship between miR-381 and BMI1 was predicted online and validated through a luciferase assay. Gain-of-functions of miR-381 and BMI1 were performed to identify their functions on BCs cell behaviors as well as tumor growth in vivo. Results miR-381 was poor regulated in BCs tissues and cells. A higher miR-381 level indicates a better prognosis of patients with BCs. Artificial up-regulation of miR-381 inhibited proliferation, invasion, migration, resistance to apoptosis, and tumor formation ability of BCs cells. miR-381 directly binds to BMI1 expression. Overexpression of BMI1 partially blocked the tumor suppressing roles of miR-381 in cell malignancy and tumor growth. In addition, miR-381 led to decreased RhoA phosphorylation and ROCK2 activation, which were also reversed by BMI1. Conclusion The study evidenced that miR-381 may act as a beneficiary biomarker in BCs patients. Up-regulation of miR-381 could suppress BCs development both in vivo and in vitro through BMI1 down-regulation and the Rho/ROCK inactivation.

scholarly journals Distinct inhibitory efficiency of siRNAs and DNAzymes to β1 integrin subunit in blocking tumor growth.

2013 ◽  
Vol 60 (1) ◽  
Author(s):  
Magdalena Wiktorska ◽  
Izabela Sacewicz-Hofman ◽  
Olga Stasikowska-Kanicka ◽  
Marian Danilewicz ◽  
Jolanta Niewiarowska
Keyword(s):  
Tumor Growth ◽  
Xenograft Model ◽  
Tumor Formation ◽  
Integrin Subunit ◽  
Β1 Integrin ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model ◽  
Intracellular Compartments

Receptors of the β1 integrin family are involved in many tumor-promoting activities. There are several approaches currently used to control integrin activity, and thus to potentially restrain tumor metastasis and angiogenesis. In this study, we compared inhibitory efficiencies of siRNA and DNAzymes against the β1 integrin subunit (DEβ1), in a mouse xenograft model. Both inhibitors were used under their most favorable conditions, in terms of concentrations, incubation time and lack of cytotoxic effects. Transfection of siRNAβ1 or DEβ1 remarkably inhibited the growth of both PC3 and HT29 colon cancer cells in vitro, and decreased their capability of initiating tumor formation in the mouse xenograft model. siRNAβ1 appeared to be slightly more efficient than DEβ1 when tested in vitro, however it was comparably less proficient in blocking the tumor growth in vivo. We conclude the DNAzyme, due to its greater resistance to degradation in extra- and intracellular compartments, to be a superior inhibitor of tumor growth in long lasting experiments in vivo when compared to siRNA, while the latter seems to be more efficient in blocking β1 expression during in vitro experiments using cell cultures.

Inhibition of Src and insulin/insulin-like growth factor-1 receptor (IR/IGF-1R) on tumors and bone turnover in prostate cancer (PCa) models in vivo compared with inhibition of either kinase alone.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 61-61
Author(s):  
Farshid Dayyani ◽  
Nila Parikh ◽  
Jian H. Song ◽  
John C. Araujo ◽  
Joan M. Carboni ◽  
...  
Keyword(s):  
Bone Turnover ◽  
Tumor Growth ◽  
Bone Turnover Markers ◽  
Bone Destruction ◽  
In Vivo Studies ◽  
Pc3 Cells ◽  
Turnover Markers ◽  
Induced Apoptosis

61 Background: The Src and IGF-1R axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are clinically promising small molecule inhibitors with high potency against Src family kinases (SFK) and IR/IGF-1R, respectively. Based on a phase I/II clinical trial in which 9/19 pts treated with docetaxel + dasatinib were increased in serum IGF-1 levels after one cycle, the aim of this study was to establish potential antitumor cooperativity of inhibiting both IGF-1R and Src in experimental PCa models in vitro and in mice. Methods: Inhibition of Src and IGF-1R pathways was accomplished by pharmacologic agents (dasatinib against Src and BMS-754807 against IR/IGF-1R) as well as by shRNA, in PC3 and LNCaP cells. In vivo studies were done after orthotopic and intratibial injection of PC3 cells in nude mice. Results: SFK inhibition decreased proliferation and migration of PCa cells whereas IGF-1R blockade induced apoptosis. All anti-tumor effects were enhanced by dual blockade. IGF-1 induced phosphorylation of Akt1 and 2. Only Akt 1 phosphorylation was decreased by dasatinib; whereas Akt 1 and 2 phosphorylation were completely abrogated by the combination. Dasatinib and BMS-754807 inhibited orthotopic in vivo tumor growth of PC3 cells more potently than either inhibitor alone. Similarly, intratibial tumor growth and bone destruction was significantly reduced with the drug combination, accompanied by a decrease in serum bone turnover markers alkaline phosphatase and N-telopeptide. Conclusions: Dual inhibition of Src and IGF-1R has greater anti-tumor effect in PCa cells compared to inhibiting either alone. In the presence of IGF-1, dasatinib and BMS-754807 are necessary to inhibit IGF-1-induced phosphorylation of Akt1 and 2 in tumor cells in culture. In intratibial models, decreased bone turnover markers in serum support the concept of targeting both the epithelial and bone microenvironment. The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking complementary processes of tumor growth and progression.

scholarly journals The Cardioprotective Protein Apolipoprotein A1 Promotes Potent Anti-tumorigenic Effects

2013 ◽  
Vol 288 (29) ◽  
pp. 21237-21252 ◽  
Author(s):  
Maryam Zamanian-Daryoush ◽  
Daniel Lindner ◽  
Thomas C. Tallant ◽  
Zeneng Wang ◽  
Jennifer Buffa ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Density Lipoprotein ◽  
Tumor Formation ◽  
Tumor Rejection ◽  
Apolipoprotein A1 ◽  
Major Protein ◽  
Tumor Growth And Metastasis

Here, we show that apolipoprotein A1 (apoA1), the major protein component of high density lipoprotein (HDL), through both innate and adaptive immune processes, potently suppresses tumor growth and metastasis in multiple animal tumor models, including the aggressive B16F10L murine malignant melanoma model. Mice expressing the human apoA1 transgene (A1Tg) exhibited increased infiltration of CD11b+ F4/80+ macrophages with M1, anti-tumor phenotype, reduced tumor burden and metastasis, and enhanced survival. In contrast, apoA1-deficient (A1KO) mice showed markedly heightened tumor growth and reduced survival. Injection of human apoA1 into A1KO mice inoculated with tumor cells remarkably reduced both tumor growth and metastasis, enhanced survival, and promoted regression of both tumor and metastasis burden when administered following palpable tumor formation and metastasis development. Studies with apolipoprotein A2 revealed the anti-cancer therapeutic effect was specific to apoA1. In vitro studies ruled out substantial direct suppressive effects by apoA1 or HDL on tumor cells. Animal models defective in different aspects of immunity revealed both innate and adaptive arms of immunity contribute to complete apoA1 anti-tumor activity. This study reveals a potent immunomodulatory role for apoA1 in the tumor microenvironment, altering tumor-associated macrophages from a pro-tumor M2 to an anti-tumor M1 phenotype. Use of apoA1 to redirect in vivo elicited tumor-infiltrating macrophages toward tumor rejection may hold benefit as a potential cancer therapeutic.

Indole-3-Carbinol Inhibits Nasopharyngeal Carcinoma

2010 ◽  
Vol 29 (2) ◽  
pp. 185-192 ◽  
Author(s):  
Wei Zhu ◽  
Wenxue Li ◽  
Guangyu Yang ◽  
Quanxin Zhang ◽  
Ming Li ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Nasopharyngeal Carcinoma ◽  
Glutathione Peroxidase ◽  
Tumor Growth ◽  
Caspase 3 ◽  
Caspase 9 ◽  
Human Nasopharyngeal Carcinoma ◽  
Induced Apoptosis

This study explored the effects of indole-3-carbinol on the proliferation of human nasopharyngeal carcinoma, both in vitro and in vivo, and the underlying mechanisms in inducing apoptosis of CNE1 cells. Proliferation, apoptosis, malondialdehyde, superoxide dismutase, glutathione peroxidase, expressions of caspase-9, and caspase-3 in human nasopharyngeal carcinoma cells CNE1 were examined. Indole-3-carbinol suppressed proliferation, induced apoptosis, decreased malondialdehyde level, increased the activity of superoxide dismutase and glutathione peroxidase, and up-regulated the expression of active fragments of caspase-9 and caspase-3 both in vitro and in vivo. It was concluded that indole-3-carbinol could inhibit proliferation and induce apoptosis of CNE1 cells and inhibit tumor growth in mice. Increased activity of superoxide dismutase and glutathione peroxidase and activated expression of caspase-9 and caspase-3 were also observed in indole-3-carbinol–treated tumors or tumor cells, suggesting that stress- and apoptosis-related molecules are involved in the indole-3-carbinol–induced apoptosis and inhibition of tumor growth.

scholarly journals CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1922
Author(s):  
Roberta Antonelli ◽  
Carlos Jiménez ◽  
Misha Riley ◽  
Tiziana Servidei ◽  
Riccardo Riccardi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Histone Deacetylase ◽  
Posterior Fossa ◽  
Histone Deacetylase Inhibitors ◽  
Pediatric Ependymoma ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response

Pediatric ependymoma (EPN) is a highly aggressive tumor of the central nervous system that remains incurable in 40% of cases. In children, the majority of cases develop in the posterior fossa and can be classified into two distinct molecular entities: EPN posterior fossa A (PF-EPN-A) and EPN posterior fossa B (PF-EPN-B). Patients with PF-EPN-A have poor outcome and are in demand of new therapies. In general, PF-EPN-A tumors show a balanced chromosome copy number profile and have no recurrent somatic nucleotide variants. However, these tumors present abundant epigenetic deregulations, thereby suggesting that epigenetic therapies could provide new opportunities for PF-EPN-A patients. In vitro epigenetic drug screening of 11 compounds showed that histone deacetylase inhibitors (HDACi) had the highest anti-proliferative activity in two PF-EPN-A patient-derived cell lines. Further screening of 5 new brain-penetrating HDACi showed that CN133 induced apoptosis in vitro, reduced tumor growth in vivo and significantly extended the survival of mice with orthotopically-implanted EPN tumors by modulation of the unfolded protein response, PI3K/Akt/mTOR signaling, and apoptotic pathways among others. In summary, our results provide solid preclinical evidence for the use of CN133 as a new therapeutic agent against PF-EPN-A tumors.

scholarly journals AEBP1 Promotes Glioblastoma Progression and Activates the Classical NF-κB Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Kai Guo ◽  
Lei Song ◽  
Jianyong Chang ◽  
Peicheng Cao ◽  
Qi Liu
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Bioinformatics Analysis ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Scratch Assay ◽  
In Vivo Experiments ◽  
Enhancer Binding Protein

Objective. Our study was aimed at investigating the mechanistic consequences of the upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in glioblastoma (GBM). Methods. The expression of AEBP1 in GBM was assessed by bioinformatics analysis and qRT-PCR; the effects of AEBP1 on GBM cell proliferation, migration, invasion, and tumor growth in vitro and in vivo were detected by a CCK-8 assay, colony formation assay, scratch assay, Transwell assay, and subcutaneous tumor formation, respectively. The activation of related signaling pathways was monitored using western blot. Results. Tumor-related databases and bioinformatics analysis revealed that AEBP1 was highly expressed in GBM and indicated poor outcome of patients; its high expression that was also confirmed in GBM tissues and cell lines was closely related to the tumor size. The results of in vitro experiments showed that AEBP1 could significantly promote GBM cell proliferation, migration, and invasion; in vivo experiments suggested that AEBP1 could contribute to the growth of GBM tumors. AEBP1 could upregulate the level of IκBα phosphorylation, decrease IκBα expression, activate the NF-κB signaling pathway, and promote the expression of downstream oncogenes. Conclusion. Upregulated AEBP1 in GBM promotes GBM cell proliferation, migration, and invasion and facilitates tumor growth in vivo by activating the classical NF-κB pathway.

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