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1.
ACS Appl Mater Interfaces ; 16(4): 4348-4360, 2024 Jan 31.
Article in English | MEDLINE | ID: mdl-38253997

ABSTRACT

Prostate cancer is the most common malignancy diagnosed in men. Androgens are directly related to its pathogenesis. Inhibition of the androgen receptor (AR) is considered to be the most promising therapeutic approach for the treatment of prostate cancer. In this study, a new type of pH-responsive dual androgen-blocking nanodrug (FASC MIPs) based on a molecularly imprinted polymer has been designed and synthesized. The nanodrug could selectively sequester testosterone from the prostate tumor through specific molecular imprinting sites and simultaneously deliver the AR inhibitory drug bicalutamide, which ultimately leads to enhanced synergistic therapy of prostate cancer. FASC MIPs demonstrate excellent pH responsiveness in a simulated tumor microenvironment due to the presence of chitosan and significantly inhibit the growth of prostate cancer cells (LNCaP cells) by blocking the G1 phase of cytokinesis. Additionally, the nanodrug also displayed excellent antitumor properties in a xenograft mouse model of prostate cancer without any sign of detrimental effects on healthy tissues and organs. Both in vitro and in vivo studies verified the augmented and synergistic therapeutic effects of FASC MIPs, and the proposed dual-androgen-blocking strategy could explore novel avenues in prostate cancer treatment.


Subject(s)
Androgens , Prostatic Neoplasms , Male , Humans , Animals , Mice , Androgens/therapeutic use , Molecularly Imprinted Polymers/therapeutic use , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Magnetic Phenomena , Hydrogen-Ion Concentration , Cell Line, Tumor , Tumor Microenvironment
2.
Int J Mol Sci ; 25(1)2023 Dec 22.
Article in English | MEDLINE | ID: mdl-38203375

ABSTRACT

Gerbera (Gerbera hybrida) is a widely cultivated ornamental plant. However, its genetic improvement is limited by the lack of genetic analysis and molecular markers for traits. In this study, we analyzed the phenotypic and genotypic variation of 140 F1 progeny from two gerbera varieties with different flower types and colors. We evaluated the flower's morphology, color, and pigment content of the F1 population and performed cluster principal component analysis (PCA) and correlation analysis. The results showed that the main ornamental traits of the hybrid progeny varied greatly. The segregation ratios of single and double flowers and ligulate and split ray florets were both 1:1. The flower colors of the F1 progeny were mainly red and purple-red, similar to the male parent's color. Furthermore, we conducted a genetic analysis of the hybrid progeny using EST-SSR markers and performed association analysis with phenotypic traits. We identified 2, 2, 3, 1, and 2 loci to be associated with peduncle length (PL), ray floret length (RFL), and outer ray floret; the level of apex relative to the top of involucre (LAI); outer corolla lips (OCL); and the b* of ray floret color, respectively. Our results reveal the genetic patterns of important ornamental traits and provide a theoretical basis and practical tools for gerbera genetic breeding.


Subject(s)
Asteraceae , Gastropoda , Animals , Plant Breeding , Flowers/genetics , Biological Variation, Population
3.
Oxid Med Cell Longev ; 2022: 5652586, 2022.
Article in English | MEDLINE | ID: mdl-35368865

ABSTRACT

Metabolic changes have been suggested to be a hallmark of tumors and are closely associated with tumorigenesis. In a previous study, we demonstrated the role of lactate dehydrogenase in regulating abnormal glucose metabolism in pituitary adenomas (PA). As the key organelle of oxidative phosphorylation (OXPHOS), mitochondria play a vital role in the energy supply for tumor cells. However, few attempts have been made to elucidate mitochondrial metabolic homeostasis in PA. Dynamin-related protein 1 (Drp1) is a member of the dynamin superfamily of GTPases, which mediates mitochondrial fission. This study is aimed at investigating whether Drp1 affects the progression of PA through abnormal mitochondrial metabolism. We analyzed the expression of dynamin-related protein 1 (Drp1) in 20 surgical PA samples. The effects of Drp1 on PA growth were assessed in vitro and in xenograft models. We found an upregulation of Drp1 in PA samples with a low proliferation index. Knockdown or inhibition of Drp1 enhanced the proliferation of PA cell lines in vitro, while overexpression of Drp1 could reversed such effects. Mechanistically, overexpressed Drp1 damaged mitochondria by overproduction of reactive oxygen species (ROS), which induced mitochondrial OXPHOS inhibition and decline of ATP production. The energy deficiency inhibited proliferation of PA cells. In addition, overexpressed Drp1 promoted cytochrome c release from damaged mitochondria into the cytoplasm and then activated the downstream caspase apoptotic cascade reaction, which induced apoptosis of PA cells. Moreover, the decreased ATP production induced by Drp1 overexpressing activated the AMPK cellular energy stress sensor and enhanced autophagy through the AMPK-ULK1 pathway, which might play a protective role in PA growth. Furthermore, overexpression of Drp1 repressed PA growth in vivo. Our data indicates that Drp1-mediated mitochondrial metabolic dysfunction inhibits PA growth by affecting cell proliferation, apoptosis, and autophagy. Selectively targeting mitochondrial metabolic homeostasis stands out as a promising antineoplastic strategy for PA therapy.


Subject(s)
Dynamins/metabolism , Pituitary Neoplasms , GTP Phosphohydrolases/metabolism , Humans , Mitochondrial Dynamics , Oxidative Phosphorylation
4.
J Biochem Mol Toxicol ; 35(8): e22835, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34057764

ABSTRACT

Transmembrane protein 88 (TMEM88) acts as a novel tumor-associated protein. The dysregulation of TMEM88 has been observed in several tumor types. However, the relevance of TMEM88 in tumorigenesis is still contradictory. This study assessed the relevance of TMEM88 in bladder cancer. TMEM88 levels were found to be significantly lower in bladder cancer tissue. Upregulation of TMEM88 resulted in a dramatic decrease in the cellular proliferative and invasive abilities of bladder cancer. Upregulation of TMEM88 decreased the level of active ß-catenin and prohibited the activation of the Wnt/ß-catenin pathway, an effect that was associated with downregulation of glycogen synthase kinase-3ß (GSK-3ß) phosphorylation. Suppression of GSK-3ß or overexpression of ß-catenin reversed the TMEM88-induced tumor-inhibiting effects in bladder cancer. Overexpression of TMEM88 prohibited the tumor formation and growth of bladder cancer cells in nude mice. In conclusion, this study demonstrates that TMEM88 exerts an antitumor function in bladder cancer through downregulation of Wnt/ß-catenin signaling.


Subject(s)
Cell Proliferation , Down-Regulation , Gene Expression Regulation, Neoplastic , Membrane Proteins/metabolism , Tumor Suppressor Proteins/metabolism , Urinary Bladder Neoplasms/metabolism , Wnt Signaling Pathway , beta Catenin/metabolism , Cell Line, Tumor , Humans , Membrane Proteins/genetics , Neoplasm Invasiveness , Tumor Suppressor Proteins/genetics , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , beta Catenin/genetics
5.
Food Chem ; 356: 129722, 2021 Sep 15.
Article in English | MEDLINE | ID: mdl-33836357

ABSTRACT

Rutin (RT), a widely distributed natural flavonoid compound, has been generally utilized as an important active ingredient owing to its considerable biomedical and economic value. Inspired by the structure features of densely-packed bayberry and well-orientated honeycomb, a novel type of magnetic molecularly imprinted polymers (HB-TI-MMIPs) with abundant high-affinity and uniformly-distributed binding sites was rationally constructed for the selective enrichment of RT from Sophora japonica. The polymerization conditions, physicochemical properties, and adsorption performance of the imprinted nanomaterials were systematically investigated. The optimized HB-TI-MMIPs display a high adsorption capacity, fast adsorption rate, and satisfactory selectivity towards RT. Meanwhile, the proposed analytical methodology using HPLC, with HB-TI-MMIPs as adsorbents, successfully applied to enrich and detect RT from Sophora japonica with high recoveries (87.2-94.6%) and good RSDs (lower than 4.3%). Therefore, the fabricated HB-TI-MMIPs with a fast magnetic responsivity and desirable adsorption performance would be attractive in plant active ingredients extraction fields.


Subject(s)
Biomimetics , Magnets/chemistry , Molecularly Imprinted Polymers/chemistry , Myrica , Rutin/chemistry , Sophora/chemistry , Adsorption , Rutin/isolation & purification , Surface Properties
6.
J Cancer ; 11(19): 5678-5688, 2020.
Article in English | MEDLINE | ID: mdl-32913462

ABSTRACT

Differential expression of TRPV1 has been detected in many cancer types, including clear cell renal cell carcinoma (ccRCC). However, the clinical significance of TRPV1 expression profile in ccRCC has not been comprehensively elucidated. In this study, TRPV1 expression in ccRCC and other cancer types was analyzed based on data from the GEO and Oncomine databases. Immunohistochemical (IHC) staining was performed for further validation in human ccRCC tissue chips. Survival and correlation analyses of TRPV1 were conducted using Kaplan-Meier Plotter (KM-Plotter) and the Tumor IMmune Estimation Resource (TIMER) database. TRPV1 exhibited a low expression profile in 2 GEO datasets (GSE6344, GSE36895) and 4 Oncomine datasets (Gumz, Lenburg, Beroukhim 1 and Beroukhim 2), as also confirmed by IHC staining. Survival analysis indicated that high enrichment of TRPV1 significantly predicted a better overall survival (OS) and disease-free survival (DFS) of 1, 3, 5 and 10 years in ccRCC patients. TIMER analysis showed that TRPV1 copy number alterations (CNA) were closely related to immune cell infiltration. The detailed results indicated that TRPV1 expression was positively correlated with the infiltration level of CD4+ T cells, but negatively correlated with B cells, macrophages, and dendritic cells infiltration. In addition, TRPV1 might also be inversely related to abundance of the regulatory T cells (Treg) and the M2 subset of macrophages. Finally, we found that TRPV1 expression was tightly associated with several key molecules of the classical pathways in ccRCC, such as VHL, TP53, HIF1A, MTOR, MAPK1, MET, CTNNB1, etc. Our research work suggests that TRPV1 is a novel tumor suppressor and prognosis marker for ccRCC and is of great value for further exploration.

7.
Biomed Res Int ; 2020: 8341097, 2020.
Article in English | MEDLINE | ID: mdl-32724813

ABSTRACT

Enzalutamide (ENZ) has been approved for the treatment of advanced prostate cancer (PCa), but some patients develop ENZ resistance initially or after long-term administration. Although a few key genes have been discovered by previous efforts, the complete mechanisms of ENZ resistance remain unsolved. To further identify more potential key genes and pathways in the development of ENZ resistance, we employed the GSE104935 dataset, including 5 ENZ-resistant (ENZ-R) and 5 ENZ-sensitive (ENZ-S) PCa cell lines, from the Gene Expression Omnibus (GEO) database. Integrated bioinformatics analyses were conducted, such as analysis of differentially expressed genes (DEGs), Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, protein-protein interaction (PPI) analysis, gene set enrichment analysis (GSEA), and survival analysis. From these, we identified 201 DEGs (93 upregulated and 108 downregulated) and 12 hub genes (AR, ACKR3, GPER1, CCR7, NMU, NDRG1, FKBP5, NKX3-1, GAL, LPAR3, F2RL1, and PTGFR) that are potentially associated with ENZ resistance. One upregulated pathway (hedgehog pathway) and seven downregulated pathways (pathways related to androgen response, p53, estrogen response, TNF-α, TGF-ß, complement, and pancreas ß cells) were identified as potential key pathways involved in the occurrence of ENZ resistance. Our findings may contribute to further understanding the molecular mechanisms of ENZ resistance and provide some clues for the prevention and treatment of ENZ resistance.


Subject(s)
Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Signal Transduction/genetics , Benzamides , Cell Line, Tumor , Computational Biology/methods , Down-Regulation/drug effects , Down-Regulation/genetics , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Gene Ontology , Gene Regulatory Networks , Hedgehog Proteins/genetics , Humans , Male , Nitriles , Phenylthiohydantoin/pharmacology , Prostate/pathology , Protein Interaction Mapping/methods , Protein Interaction Maps/drug effects , Protein Interaction Maps/genetics , Up-Regulation/drug effects , Up-Regulation/genetics
8.
Colloids Surf B Biointerfaces ; 182: 110375, 2019 Oct 01.
Article in English | MEDLINE | ID: mdl-31351268

ABSTRACT

To overcome the limited drug loading capacity of magnetic nanopharmaceuticals arising from the relatively large mass of the metal core, a high-loading drug delivery system based on amino-functionalized Fe3O4 magnetic nanospheres modified by hyperbranched phenylboronic acid (HPBA-Fe3O4) were prepared for the first time. The obtained nanomaterials were characterized by transmission electron microscopy, Fourier transform infrared, zeta potential, elemental analysis, vibrating sample magnetometry and X-ray diffraction analysis, and the results showed that hyperbranched phenylboronic acid (HPBA) were successfully grafted onto the surface of the magnetic nanospheres. The polymerization conditions, adsorption and desorption performance, and tumor-targeting ability of HPBA-Fe3O4 was investigated in detail through chemical and biological experiments. The drug loading amount and capacity of HPBA-Fe3O4 are 271.3 mg/g and 27.13%, respectively, which are 2.26 and 3.27 times greater than those of PBA-Fe3O4 and PEI-Fe3O4, and the thermodynamic fitting results further demonstrate the high drug loading ability of HPBA-Fe3O4. In vitro studies performed in U-87 MG malignant glioma cells and astrocytes via light and fluorescence microscopy analyses, cell counting kit-8 assays, and HPLC tests confirm the pH-sensitive release and tumor-targeted drug delivery capabilities of HPBA-Fe3O4. The facile fabrication of hyperbranched magnetic nanomaterials could be an alternative solution for designing high-loading, tumor cell-targeting and pH-responsive DDSs with high-mass cores.


Subject(s)
Boronic Acids/chemistry , Doxorubicin/administration & dosage , Drug Delivery Systems/methods , Ferrosoferric Oxide/chemistry , Magnetite Nanoparticles/chemistry , Neoplasms/metabolism , Animals , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacokinetics , Cell Line, Tumor , Cell Survival/drug effects , Cells, Cultured , Doxorubicin/chemistry , Doxorubicin/pharmacokinetics , Humans , Hydrogen-Ion Concentration , Magnetite Nanoparticles/ultrastructure , Mice , Microscopy, Electron, Transmission , Neoplasms/drug therapy , Neoplasms/pathology , Spectroscopy, Fourier Transform Infrared
9.
Cancer Med ; 8(10): 4792-4805, 2019 08.
Article in English | MEDLINE | ID: mdl-31250978

ABSTRACT

AIM: JQ1, a BET bromodomain inhibitor, is a promising therapeutic approach for bladder cancer (BC). Our study aimed to determine whether autophagy is induced by JQ1 and its potential role toward proliferation in BC. METHODS: Cell proliferation was determined by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, cell counting assay, and colony formation assay. Autophagosomes and autolysosomes were observed by transmission electron microscopy and mRFP-EGFP-LC3 fluorescence assay. 3-MA, BAFA1, NH4 Cl, and siATG5 were used to inhibit autophagy. AMPK siRNA was used to knock down AMPK. T24 xenograft model in mice was chosen to perform in vivo studies. Autophagy markers LC-3B and p62, p-AMPKα, p-ACC, p-ULK1, p-mTOR and p-LKB1 were determined by western blot in vitro studies and by immunohistochemistry (IHC) in vivo specimens. RESULTS: We found that BC cell proliferation was suppressed by JQ1; moreover, JQ1 induced the accumulation of autophagosomes and autolysosomes, and autophagy flux, and the growth suppression capacity of JQ1 was attenuated by autophagy inhibitors. Furthermore, we found that JQ1 induced the phosphorylation of AMPKα, and AMPKα knockdown attenuated autophagy induction and anti-proliferation effect induced by JQ1 in BC cells, indicating that autophagy induced by JQ1 is dependent on AMPKα. Through endogenous immunoprecipitation analysis, we found that JQ1 dramatically increased the interaction between LKB1 and AMPKα, which may lead to more AMPK activation. Proliferation inhibition, autophagy induction, and LKB1/AMPK activation capacities of JQ1 were further confirmed in vivo. CONCLUSIONS: Taken together, our results demonstrate that autophagy is induced by JQ1 through activation of LKB1/AMPK pathway, and the autophagy induced by JQ1 positively contributes to the inhibition of BC cell proliferation. These findings provide a novel point of view to understand the mechanism of how targeting BET bromodomain suppress cancer cell growth and suggest that targeting BET bromodomain might be a potential approach to treat BC in the future.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Azepines/administration & dosage , Protein Serine-Threonine Kinases/metabolism , Triazoles/administration & dosage , Urinary Bladder Neoplasms/drug therapy , AMP-Activated Protein Kinase Kinases , AMP-Activated Protein Kinases/genetics , Animals , Autophagy , Azepines/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Gene Knockdown Techniques , Humans , Mice , Phosphorylation , Triazoles/pharmacology , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathology , Xenograft Model Antitumor Assays
10.
J Colloid Interface Sci ; 552: 142-152, 2019 Sep 15.
Article in English | MEDLINE | ID: mdl-31121431

ABSTRACT

In this work, a novel amphiphilic magnetic nanocomposite (Fe3O4@A-O) used for the adsorption of phthalate esters was synthesized by a simple sol-gel surface modification method, during which hydrophilic amino groups of 3-aminopropyltriethoxylsilane and hydrophobic alkyl chains of N-octyltrimethoxysilane were modified onto Fe3O4 nanoparticles. Morphologies and surface structures of as-prepared magnetic nanomaterials were characterized in detail. The preparation, adsorption, and desorption conditions of Fe3O4@A-O were investigated systematically and the adsorption mechanism was discussed. The Fe3O4@A-O exhibits quite fast adsorption for six phthalate esters, which only takes two minutes and is 10 ∼ 720 times shorter than other reported adsorbents. Theoretical adsorption capacities of Fe3O4@A-O for dibutyl phthalate, dihexyl phthalate, dioctyl phthalate, and didecyl phthalate are >1000 mg/g according to the Freundlich fitting. With ethanol as desorption solvent, it only takes one minute to reach desorption equilibrium. In addition, Fe3O4@A-O can be collected from aqueous solution with an applied magnet in just three seconds, and it shows satisfactory stability and reusability after recycling 10 times. The developed amphiphilic adsorbent exhibits great promises in the removal of phthalate esters because of its easy preparation, excellent adsorption and desorption performances, rapid magnetic separation, and good reusability.

11.
Oncol Rep ; 40(6): 3543-3550, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30272315

ABSTRACT

Transforming growth factor (TGF)­ß1 is highly expressed in bladder transitional cell carcinoma (TCC) and is positively associated with tumor grade. TGF­ß1 signaling promotes cell metastasis by inducing epithelial­mesenchymal transition (EMT), however, the underlying mechanisms are not fully understood. Our previous study demonstrated the anti­metastatic effects of silibinin, a natural flavonoid derived from milk thistle, against TCC. The present study investigated the effects of silibinin on TGF­ß1­induced EMT in TCC, focusing on the role of prostaglandin­endoperoxide synthase 2 (COX­2). Cell migration was determined by a wound healing assay and Transwell migration assay, and cell invasion was investigated using a Transwell invasion assay. Cell morphology was observed using an inverted microscope. Cell viability was evaluated by an MTT and cell counting assays. EMT markers were detected by reverse transcription­quantitative polymerase chain reaction and western blotting. Specific small interfering RNA was used to knockdown COX­2 gene expression. TGF­ß1 promoted cell migration and invasion, induced EMT and upregulated the expression of COX­2. COX­2 knockdown attenuated TGF­ß1­induced EMT, indicating that COX­2 upregulation was essential for TGF­ß1­induced EMT. Silibinin attenuated TGF­ß1­induced migration and invasion by inhibiting EMT, and was associated with COX­2 downregulation. TGF­ß1­induced COX­2 upregulation, which was inhibited by silibinin. In addition, TGF­ß1­induced EMT was further inhibited when silibinin treatment was combined with COX­2­knockdown. The results suggested that silibinin may be a potential future treatment for metastatic TCC.


Subject(s)
Carcinoma, Transitional Cell/metabolism , Cyclooxygenase 2/metabolism , Silybin/pharmacology , Transforming Growth Factor beta1/pharmacology , Urinary Bladder Neoplasms/metabolism , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/genetics , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclooxygenase 2/genetics , Down-Regulation/drug effects , Epithelial-Mesenchymal Transition/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Neoplasm Invasiveness , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics
12.
Talanta ; 181: 271-277, 2018 May 01.
Article in English | MEDLINE | ID: mdl-29426512

ABSTRACT

Novel water-compatible magnetic molecularly imprinted polymers were developed. The magnetic core was firstly grafted by methyl acrylate and ethanediamine to increase the number of amino groups, which could immobilize more templates and form high-density recognition sites. Dopamine was adopted as functional monomer and crosslinker to retighten templates and prepare hydrophilic polymers. The characterization, adsorption capability, selectivity, and reusability were investigated in detail. The limit of detection and quantification of the method were 0.01µgmL-1 and 0.038µgmL-1. The experimental results exhibited that the resultant nanomaterials had high crystallinity, satisfactory magnetic property, fast kinetics, favorable adsorption capacity, excellent specificity, and pleasing recovery after a mild elution. In addition, the recoveries of the proposed method at four spiked levels analysis were between 98.4% to 101.3%. The obtained imprinted nanoparticles were used as sorbents for selective separation and determination of chlorogenic acid in Honeysuckle tea.


Subject(s)
Chlorogenic Acid/analysis , Lonicera/chemistry , Magnetite Nanoparticles/chemistry , Molecular Imprinting , Polymers/chemistry , Tea/chemistry , Adsorption , Chlorogenic Acid/chemistry , Chlorogenic Acid/isolation & purification , Kinetics , Magnetic Phenomena , Magnetics , Magnetite Nanoparticles/ultrastructure , Reproducibility of Results , Spectroscopy, Fourier Transform Infrared , Surface Properties , X-Ray Diffraction
13.
J Colloid Interface Sci ; 515: 18-26, 2018 Apr 01.
Article in English | MEDLINE | ID: mdl-29324271

ABSTRACT

Novel magnetic molecularly imprinted nanomaterials (DA + BSA-MMIPs) were prepared adopting bovine serum albumin (BSA) and dopamine as bifunctional monomers for the first time. Besides the role of assistant functional monomer, BSA can exclude the proteins with like charges and promote low molecular weight tetracyclines to be adsorbed. Thus, the DA + BSA-MMIPs could fulfil the selective separation of tetracyclines directly from milk samples. The characteristics, polymerization conditions, and adsorption performances of the resultant nanomaterials were investigated in detail. In addition of uniform imprinting layers, stable crystalline phase, and good magnetism of the DA + BSA-MMIPs, they have rapid binding kinetic, high adsorption capacity, and favorable reusability. The imprinted nanomaterials were coupled with HPLC to selectively extract and determine trace tetracyclines from untreated milk samples. The recoveries of tetracyclines are in the range of 84.1-95.8% with relative standard deviations of less than 6.7%. The developed method is especially suitable for the selective enrichment and detection of target compounds directly from a complex sample with proteins.

14.
Oncol Rep ; 39(1): 101-108, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29138866

ABSTRACT

High-mobility group AT-hook 2 (HMGA2), a member of the high mobility group family, has been reported to correlate with cancer progression. However, there is no report concerning the correlation between HMGA2 and metastasis in renal cell carcinoma. In the present study, we found that HMGA2 was highly expressed in five renal cell carcinoma cell lines compared with that in the normal renal tubular epithelial HK2 cell line. Additionally, HMGA2 facilitated cell migration and invasion of renal cell carcinoma cells, as evidenced by wound healing and Transwell assays. Subsequently, our results revealed that the E­cadherin level was upregulated, while N­cadherin, Twist1 and Twist2 expression were downregulated in HMGA2-depleted ACHN cells. In contrast, overexpression of HMGA2 in 786­O cells enhanced epithelial-mesenchymal transition (EMT). In addition, analysis of the database Cancer Browser further validated the positive correlation between HGMA2 and Twist1 or Twist2 in renal cell carcinoma. Meanwhile, Kaplan-Meier analysis indicated that low HMGA2 expression was closely associated with an increased overall survival in renal cell carcinoma patients. To confirm the underlying mechanism of HMGA2-regulated EMT, our results revealed that silencing of HMGA2 downregulated the mRNA and protein levels of TGF-ß and Smad2, while HMGA2 overexpression had the opposite effect. Furthermore, TGF-ß overexpression could partially reverse the anti-metastatic effect and mesenchymal-epithelial transition (MET) by HMGA2 loss, while TGF-ß deficiency impeded the pro­metastatic phenotype and high expression of EMT markers induced by HMGA2 overexpression. In summary, our results demonstrated that HMGA2 facilitated a metastatic phenotype and the EMT process in renal cell carcinoma cells in vitro through a TGF-ß-dependent pathway. In addition, these data strongly suggest that HGMA2 may serve as a potential therapeutic target and prognostic biomarker against renal cell carcinoma in the future.


Subject(s)
Carcinoma, Renal Cell/metabolism , HMGA2 Protein/metabolism , Kidney Neoplasms/metabolism , Smad2 Protein/metabolism , Transforming Growth Factor beta/metabolism , Carcinoma, Renal Cell/genetics , Cell Line, Tumor , Cell Movement , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/genetics , Neoplasm Invasiveness , Signal Transduction , Smad2 Protein/genetics , Transforming Growth Factor beta/genetics , Up-Regulation
15.
Oncotarget ; 8(49): 86277-86286, 2017 Oct 17.
Article in English | MEDLINE | ID: mdl-29156794

ABSTRACT

Currently only docetaxel has been approved to be used in the chemotherapy of prostate cancer and new drugs are urgent need. Salen-Mn is a novel type of synthetic reagent bionic and exerts remarkable anticancer activities. However, the effect of Salen-Mn on human prostate cancer has not been elucidated yet. In this study, we found that treatment of PC-3 and DU145 human prostate cancer cells with Salen-Mn inhibited cell growth in dose and time dependent manner. Moreover, Salen-Mn induced cell apoptosis, and increased the expression of apoptotic proteins, such as cleaved caspase-3, cleaved PARP, and Bax, in PC-3 and DU145 prostate cancer cells. Furthermore, we found that Salen-Mn induced expression of LC3-I/II, which is protein marker of cell autophagy, in both dose and time dependent manners; in addition, Salen-Mn increased the phosphorylation of AMPK, suggesting that Salen-Mn increase cell autophagy through activating AMPK pathway. On the other hand, when PC-3 and DU145 cells were treated with Salen-Mn and 3-MA, an inhibitor of cell autophagy, the inhibitory effect of Salen-Mn on cell growth and the induction of apoptotic proteins were decreased. In addition, we found that Salen-Mn inhibited the growth of PC-3 cell xenografts in nude mice. In summary, our results indicate that Salen-Mn suppresses cell growth through inducing AMPK activity and autophagic cell death related cell apoptosis in prostate cancer cells and suggest that Salen-Mn and its derivatives could be new options for the chemical therapeutics in the treatment of prostate cancer.

16.
Oncol Lett ; 14(2): 1847-1854, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28789420

ABSTRACT

Krüppel-like factor 5 (KLF5) is frequently deleted and inactivated in prostate cancer, and exerts tumor-suppressing function in prostate cancer cells. However, the function of KLF5 in the apoptosis of prostate cancer cells remains unclear. In the present study, the effect of KLF5 on phorbol 12-myristate 13-acetate (PMA)-induced apoptosis was investigated in prostate cancer LNCaP cells. It was demonstrated that PMA induced the expression of KLF5 at the mRNA and protein level. To identify whether KLF5 regulates the activity of the downstream pathway, stable KLF5 knockdown or overexpression cell lines were constructed with lentivirus harboring shRNA targeting KLF5 or full-length KLF5 in LNCaP cells. Knockdown of KLF5 significantly decreased PMA-induced apoptosis, while cell apoptosis was significantly increased following KLF5 overexpression compared with the corresponding control groups. Consistently, expression of cleaved poly(ADP-ribose) polymerase and caspase-3 induced by PMA was decreased following KLF5 knockdown and increased following KLF5 overexpression. Using the control medium from cells treated with PMA, it was demonstrated that KLF5 is required for the control medium to induce apoptosis. c-Jun N-terminal kinase (JNK) activity is essential for the apoptosis induced by PMA. It was revealed that knockdown of KLF5 decreased, while overexpression of KLF5 increased the phosphorylation of JNK induced by PMA and control medium treatment. Furthermore, inhibition of tumor necrosis factor α (TNFα) decreased KLF5 expression and significantly decreased cell apoptosis induced by PMA, and control medium. This data indicates that KLF5 is essential for the apoptosis induced by PMA in LNCaP prostate cancer cells. Furthermore, KLF5 is essential for activity of the autocrine factor TNFα, which is secreted by cells treated with PMA and mediates the function of PMA-induced apoptosis through regulating the activity of JNK signaling pathway. These results provide novel insights into the complexity of the signaling pathways regulating apoptosis in prostate cancer cells, which could aid in the development of novel treatments for patients with prostate cancer.

17.
Int J Nanomedicine ; 12: 2979-2993, 2017.
Article in English | MEDLINE | ID: mdl-28442907

ABSTRACT

PURPOSE: Androgen plays an important role in the progression of prostate cancer. In the present study, novel magnetic molecularly imprinted polymers (MMIPs) with good biocompatibility were produced for the selective separation and inhibition of testosterone in prostate cancer cells. MATERIALS AND METHODS: MMIPs were prepared by using magnetic nanospheres, gelatin, and testosterone as the supporting materials, functional monomer, and the template molecule, respectively. The characterization of the resultant products was investigated by transmission electron microscopy, X-ray diffraction, and vibrating sample magnetometry. To test whether MMIPs can remove testosterone in biologic samples, human LNCaP (androgen-dependent) and C4-2 (androgen-independent) prostate cancer cells were selected as cell models. The translocation of androgen receptor (AR) was detected by immunofluorescence assay, and the expression of PSA mRNA was detected by real-time quantitative polymerase chain reaction analysis. Cell flow cytometry analysis was performed to detect cell cycle arrest. RESULTS: The synthesized nanomaterials (MMIPs) possessed high crystallinity, satisfactory superparamagnetic properties, and uniform imprinted shell, and exhibited high adsorption capacity, fast kinetics, and high selectivity for testosterone. Moreover, the obtained imprinted nanomaterials could selectively enrich and detect testosterone in the LNCaP cell samples as a solid-phase extractant coupled with high-performance liquid chromatography. In addition, the MMIPs could freely enter prostate cancer cells and suppress the translocation of AR into the cell nucleus. We further found that MMIPs inhibited upregulation of AR downstream target genes in LNCaP and C4-2 cells; also, MMIPs inhibited cell growth and induced obvious cell cycle arrest in androgen-dependent LNCaP cells, but had no obvious effect on androgen-independent C4-2 cells. CONCLUSION: Our results indicate that the obtained imprinted nanomaterials can specifically and effectively bind testosterone and recover it from prostate cancer cells. Moreover, the MMIPs can freely enter prostate cancer cells and block the activation of testosterone-AR pathway. Thus, the MMIPs may be a new option for antiandrogen therapy in prostate cancer.


Subject(s)
Molecular Imprinting/methods , Polymers/pharmacology , Prostatic Neoplasms/metabolism , Testosterone/isolation & purification , Adsorption , Biocompatible Materials , Cell Line, Tumor , Chromatography, High Pressure Liquid , Ferrous Compounds/chemistry , Humans , Magnetics , Magnetometry/methods , Male , Microscopy, Electron, Transmission , Polymers/chemistry , Prostatic Neoplasms/drug therapy , Solid Phase Extraction , Testosterone/metabolism , X-Ray Diffraction
18.
Oncotarget ; 7(25): 37868-37881, 2016 Jun 21.
Article in English | MEDLINE | ID: mdl-27191265

ABSTRACT

LncRNA DANCR suppresses differentiation of epithelial cells, however, its function in prostate cancer development is still unknown. In the present study, we found the expression of DANCR increases in prostate cancer tissues and cells compared to normal prostate tissues and cells, moreover, DANCR promotes invasion and migration of prostate cancer cells in vitro and metastasis of tumor xenografts in nude mice. Mechanistically, we found that TIMP2/3, which are critical metastasis inhibitor of prostate cancer, were down-regulated by DANCR synergistically with EZH2 through epigenetically silencing their promoter by chromatin immunoprecipitation assay. In addition, we further investigated whether DANCR is regulated by the differentiation-promoting androgen-androgen receptor (AR) pathway and found that DANCR expression is repressed by androgen-AR; furthermore, DANCR impedes the upregulation of TIMP2/3 and the suppression of invasion and migration by androgen-AR. On the other hand, interestingly, we found that in prostate cancer cells DANCR knockdown decreased the promotion of invasion and migration by the treatment of enzalutamide, which is an AR inhibitor. In summary, our results indicate that DANCR promotes prostate cancer invasion and metastasis through repressing the expression of TIMP2/3, and suggest that DANCR could be a potential target for preventing prostate cancer metastasis, and knockdown DANCR may lessen the potential side effect of AR inhibitor.


Subject(s)
Epigenesis, Genetic , Prostatic Neoplasms/metabolism , RNA, Long Noncoding/genetics , Tissue Inhibitor of Metalloproteinase-2/metabolism , Tissue Inhibitor of Metalloproteinase-3/metabolism , Animals , Benzamides , Cell Line, Tumor , Cell Movement , Enhancer of Zeste Homolog 2 Protein/metabolism , Gene Silencing , Humans , Male , Mice , Mice, Nude , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Transplantation , Nitriles , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/pharmacology , Promoter Regions, Genetic , RNA, Long Noncoding/metabolism , Receptors, Androgen/metabolism
19.
J Sep Sci ; 39(14): 2876-83, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27234958

ABSTRACT

We report a core-shell magnetic molecularly imprinted polymer with high affinity through a facile sol-gel method for the selective adsorption of bovine hemoglobin from real bovine blood. Copper ions grafted on the surface of the matrix could immobilize template protein through chelation, which greatly enhances the orderliness of imprinted cavities and affinity of polymers. The obtained products exhibit a desired level of magnetic susceptibility, resulting in the highly efficient adsorption process. The results of adsorption experiments show that the saturation adsorption capacity of imprinted products could reach 116.3 mg/g within 30 min. Meanwhile, the specific binding experiment demonstrates the high selectivity of polymers for bovine hemoglobin. Furthermore, satisfactory reusability is demonstrated by ten adsorption-desorption cycles with no obvious deterioration in binding capacity. Electrophoretic analysis suggests the polymer could be used successfully in separation and enrichment of bovine hemoglobin from the bovine blood sample, which exhibits potential application in pretreatment of proteomics.


Subject(s)
Chelating Agents/chemistry , Copper/chemistry , Hemoglobins/isolation & purification , Magnetite Nanoparticles/chemistry , Molecular Imprinting , Polymers/chemistry , Adsorption , Animals , Cattle , Hemoglobins/chemistry , Surface Properties
20.
Urol Oncol ; 34(2): 58.e11-8, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26480897

ABSTRACT

OBJECTIVES: Krüppel-like factor 5 (KLF5) modulates multiple cell processes in different cancers. It is frequently deleted and inactivated in prostate cancer and may exert a tumor suppressor function. However, how KLF5 inhibits the progression of prostate cancer is still not clear. In the present study, we identified how KLF5 and tumor necrosis factor α (TNFα) pathway, which can induce apoptosis in cancer, regulate each other in LNCaP prostate cancer cells. MATERIAL AND METHODS: The expression of messenger RNA and protein was detected by real-time polymerase chain reaction assay and western blot analysis, respectively. To identify whether KLF5 regulates the activity of TNFα downstream pathway, we constructed a stable KLF5 knockdown or KLF5 overexpressing cell line with lentivirus-containing short hairpin RNA targeting KLF5 or full-length KLF5 in LNCaP cells. Cell apoptosis was determined through flow cytometry assay. In addition, the regulation of KLF5 on target gene transcription was detected by reporter luciferase activity assay, and the binding of KLF5 on target promoter was detected through oligonucleotides pull-down analysis. RESULTS: We found that TNFα induced the expression of KLF5 at both messenger RNA and protein levels; moreover, TNFα up-regulated KLF5 through TNF receptor 1 but not through TNF receptor 2 in LNCaP cells. Knockdown of KLF5 decreased apoptosis induced by TNFα, whereas cell apoptosis was increased by KLF5 overexpression. Consistently, expression of cleaved PARP and caspase-3 induced by TNFα was decreased by KLF5 knockdown, whereas it was increased by overexpressed KLF5. JNK activity is essential for the apoptosis induced by TNFα. We found that knockdown of KLF5 not only decreased the phosphorylation of JNK induced by TNFα, but also down-regulated the transcription of mitogen-activated protein kinase kinase 7 (MKK7), an upstream kinase of JNK, by binding to the MKK7 promoter. CONCLUSIONS: Our results indicate that KLF5 is an essential transcription regulator of MKK7 kinase and promotes the apoptosis induced by TNFα in LNCaP cells. Loss of KLF5 in prostate cancer may decrease cell response to TNFα-inducing apoptosis and facilitate cancer initiation and progression; moreover, KLF5 could be a potential molecular marker for predicting the effect of high-dose TNFα on tumor growth inhibition in prostate cancer.


Subject(s)
MAP Kinase Kinase 7/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , RNA, Messenger/genetics , Apoptosis , Cell Line, Tumor , Humans , Kruppel-Like Transcription Factors , Male , Middle Aged , Tumor Necrosis Factor-alpha , Up-Regulation
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