Heparanase inhibitor OGT 2115 induces prostate cancer cell apoptosis via the downregulation of MCL­1.

Heparanase (HPSE), an endo-ß-D-glucuronidase, cleaves heparan sulfate and serves an important role in the tumor microenvironment and thus in tumorigenesis. HPSE is known to promote tumor cell evasion of apoptosis. However, the underlying mechanism of this requires further study. In the present study, the results demonstrated that myeloid cell leukemia-1 (MCL-1), an antiapoptotic protein, and HPSE were upregulated in prostate cancer tissues compared with adjacent normal tissues. In addition, the HPSE inhibitor, OGT 2115, inhibited PC-3 and DU-145 prostate cancer cell viability in a dose-dependent manner, with IC50 values of 20.2 and 97.2 µM, respectively. Furthermore, annexin V/PI double-staining assays demonstrated that OGT 2115 induced apoptosis in prostate cancer cells. OGT 2115 treatment markedly decreased MCL-1 protein expression levels, whereas RNA interference-mediated downregulation of MCL-1 and OGT 2115 drug treatment synergistically induced apoptosis in PC-3 and DU-145 cells. In vivo, OGT 2115 40 mg/kg (ig) significantly inhibited PC-3 cell xenograft growth in nude mice and increased the positive TUNEL staining rate of xenograft tissues. It was therefore hypothesized that MCL-1 was an important signaling molecule in OGT 2115-induced apoptosis. The results of the present study also demonstrated that the proteasome inhibitor, MG-132, markedly inhibited the downregulation of MCL-1 protein expression levels induced by OGT 2115. However, the protein synthesis inhibitor, cycloheximide, did not affect the role of OGT 2115 in regulating MCL-1. In summary, the results of the present study demonstrated that the proapoptotic activity of OGT 2115 was achieved by downregulating MCL-1.

The Specifically Androgen-Regulated Gene (SARG) Promotes Papillary Thyroid Carcinoma (PTC) Lymphatic Metastasis Through Vascular Endothelial Growth Factor C (VEGF-C) and VEGF Receptor 3 (VEGFR-3) Axis.

The papillary thyroid carcinoma (PTC) metastasizes through lymphatic spread, but the follicular thyroid cancer (FTC) metastasis occurs by following hematogenous spread. To date, the molecular mechanism underlying different metastatic routes between PTC and FTC is still unclear. Here, we showed that specifically androgen-regulated gene (SARG) was significantly up-regulated in PTC, while obviously down-regulated in FTC through analyzing the Gene Expression Omnibus (GEO) database. Immunohistochemistry assay verified that the PTC lymph node metastasis was associated with higher levels of SARG protein in clinical PTC patient samples. SARG-knockdown decreased TPC-1 and CGTH-W3 cells viability and migration significantly. On the contrary, SARG-overexpressed PTC cells possessed more aggressive migratory ability and viability. In vivo, SARG overexpression dramatically promoted popliteal lymph node metastasis of xenografts from TPC-1 cells mouse footpad transplanting. Mechanistically, SARG overexpression and knockdown significantly increased and decreased the expression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor 3 (VEGFR-3), respectively, thereby facilitating or inhibiting the tube formation in HUVECs. The tube formation experiment showed that SARG overexpression and knockdown promoted or inhibited the number of tube formations in HUVEC cells, respectively. Taken together, we showed for the first time the differential expression profile of SARG between PTC and FTC, and SARG promotes PTC lymphatic metastasis via VEGF-C/VEGFR-3 signal. It indicates that SARG may represent a target for clinical intervention in lymphatic metastasis of PTC.

Transmembrane 4 L Six Family Member 1 Suppresses Hormone Receptor--Positive, HER2-Negative Breast Cancer Cell Proliferation.

Background: The prognosis of breast cancer varies according to the molecular subtype. Transmembrane 4 L six family 1 (TM4SF1) exhibits different expression patterns among the molecular subtypes of breast cancer. However, the expression profile of TM4SF1 in hormone receptor HR+HER2- breast cancer remains unclear. Methods: TM4SF1 mRNA levels were examined in major subclasses of breast cancer by analyzing The Cancer Genome Atlas (TCGA) datasets. In addition, TM4SF1 protein and mRNA levels in HR+HER2- breast cancer tissue samples were determined by immunohistochemistry and Western blot assay. The effect of TM4SF1 on cell proliferation was evaluated using MTT, colony formation, 3D organoid, and xenograft models, following the TM4SF1 overexpression or knockdown. Results: TCGA database analysis demonstrated that TM4SF1 was downregulated in breast cancer compared with the healthy adjacent breast tissue. In addition, the expression of TM4SF1 in basal-like one and the mesenchymal TNBC tissue was higher than that of the healthy adjacent breast tissue. Other types, including the luminal androgen receptor-positive TNBC tissue, expressed lower levels of TM4SF1. Immunohistochemistry and real-time quantitative PCR assays demonstrated that the TM4SF1 protein and mRNA levels were downregulated in the HR+HER2- breast cancer tissue compared with the healthy adjacent tissue. Moreover, the TM4SF1 overexpression reduced the viability of MCF-7 and ZR-75-1 breast cancer cells, whilst reducing the number of colonies and 3D-organoids formed by these cell lines. By contrast, TM4SF1 knockdown led to an increased MCF-7 cell proliferation. However, in the TNBC cell line, MDA-MB-231, TM4SF1 silencing reduced cell proliferation. In vivo, the TM4SF1 overexpression inhibited MCF-7 xenograft growth in a nude mouse model, which was associated with the downregulation of the Ki-67 expression, apoptosis induction, and inhibition of the mTOR pathway. Conclusion: TM4SF1 is downregulated in HR + HER2-breast cancer, and the overexpression of TM4SF1 suppresses cell proliferation in this cancer subtype.

XMD-17-51 Inhibits DCLK1 Kinase and Prevents Lung Cancer Progression.

Doublecortin-like kinase 1 (DCLK1) is a cancer stem cell marker that is highly expressed in various types of human cancer, and a protein kinase target for cancer therapy that is attracting increasing interest. However, no drug candidates targeting DCLK1 kinase have been developed in clinical trials to date. XMD-17-51 was found herein to possess DCLK1 kinase inhibitory activities by cell-free enzymatic assay. In non-small cell lung carcinoma (NSCLC) cells, XMD-17-51 inhibited DCLK1 and cell proliferation, while DCLK1 overexpression impaired the anti-proliferative activity of XMD-17-51 in A549 cell lines. Consequently, XMD-17-51 decreased Snail-1 and zinc-finger-enhancer binding protein 1 protein levels, but increased those of E-cadherin, indicating that XMD-17-51 reduces epithelial-mesenchymal transition (EMT). Furthermore, sphere formation efficiency was significantly decreased upon XMD-17-51 treatment, and XMD-17-51 reduced the expression of stemness markers such as ß-catenin, and pluripotency factors such as SOX2, NANOG and OCT4. However, the percentage of ALDH+ cells was increased significantly following treatment with XMD-17-51 in A549 cells, possibly due to EMT inhibition. In combination, the present data indicated that XMD-17-51 inhibited DCLK1 kinase activity in a cell-free assay with an IC50 of 14.64 nM, and decreased DCLK1 protein levels, cell proliferation, EMT and stemness in NSCLC cell lines. XMD-17-51 has the potential to be a candidate drug for lung cancer therapy.

LPAR5 promotes thyroid carcinoma cell proliferation and migration by activating class IA PI3K catalytic subunit p110ß.

Lysophosphatidic acid receptor 5 (LPAR5) is involved in mediating thyroid cancer progression, but the underlying mechanism needs to be further revealed. In this study, we confirmed that LPAR5 is upregulated in papillary thyroid carcinoma (PTC), especially in BRAF-like PTC, by analyzing The Cancer Genome Atlas (TCGA) database and performing immunohistochemistry assay in human thyroid cancer tissues. LPAR5-specific antagonist TC LPA5 4 treatment inhibited CGTH-W3, TPC-1, B-CPAP, and BHT-101 cell proliferation, CGTH-W3 and TPC-1 cell migration significantly. In vivo, TC LPA5 4 treatment could delay CGTH-W3 xenograft growth in nude mice. We also found that LPAR5-specific antagonist TC LPA5 4, PI3K inhibitor wortmannin, or mTOR inhibitor rapamycin pretreatment abrogated phosphorylation of Akt and p70S6K1 stimulated by LPA in CGTH-W3 and TPC-1 cells. Stimulating CGTH-W3 cells transfected with pEGFPC1-Grp1-PH fusion protein with LPA resulted in the generation of phosphatidylinositol (3,4,5)-triphosphate, which indicates that PI3K was activated by LPA directly. The p110ß-siRNA instead of p110α-siRNA transfection abrogated the increase of levels of phosphorylated Akt and S6K1 stimulated by LPA. Furthermore, immunoprecipitation assay confirmed an interaction between LPAR5 and p110ß. Overall, we provide new insights that the downregulation of LPAR5 decreased the proliferation and migration phenotype via the PI3K/Akt pathway. Inhibition of LPAR5 or the PI3K/Akt signal may be a novel therapeutic strategy for treating thyroid cancer.

Role of oncogenic REGγ in cancer.

Cancer is a critical global health-care problem with limited therapeutic options. Since cancers are life-threatening illnesses, the identification of a promising oncotarget and its clinical correlates are relevant. Mounting evidence has emerged indicating that REG gamma (REGγ), a member of the 11S proteasome activators, plays a pivotal role in the development of multiple human cancers. However, an elaborate summary on the association between REGγ and cancer is still lacking. In this Review, we discuss how REGγ, through its ATP- and ubiquitin-independent manners, represents a promising cancer biomarker and therapeutic oncotarget for multiple human cancers. Aberrant REGγ expression closely associated with tumorigenesis attributes to its biological functions for controlling and regulating cell cycle, proliferation, migration, invasion, angiogenesis, and metastasis of the cancer cells by degrading proteins of cytosol and nucleus in the eukaryotic cells. REGγ serves as a molecular switch to activate multifarious oncogenic signaling pathways, such as MAPK/p38, TGF-ß/Smad, and Wnt/ß-catenin. The review describes that targeting REGγ may provide new diagnostic and therapeutic applications in cancer.

High-Performance Cathode Material of FeF3·0.33H2O Modified with Carbon Nanotubes and Graphene for Lithium-Ion Batteries.

The FeF3·0.33H2O cathode material can exhibit a high capacity and high energy density through transfer of multiple electrons in the conversion reaction and has attracted great attention from researchers. However, the low conductivity of FeF3·0.33H2O greatly restricts its application. Generally, carbon nanotubes (CNTs) and graphene can be used as conductive networks to improve the conductivities of active materials. In this work, the FeF3·0.33H2O cathode material was synthesized via a liquid-phase method, and the FeF3·0.33H2O/CNT + graphene nanocomposite was successfully fabricated by introduction of CNTs and graphene conductive networks. The electrochemical results illustrate that FeF3·0.33H2O/CNT + graphene nanocomposite delivers a high discharge capacity of 234.2 mAh g-1 in the voltage range of 1.8-4.5 V (vs. Li+/Li) at 0.1 C rate, exhibits a prominent cycling performance (193.1 mAh g-1 after 50 cycles at 0.2 C rate), and rate capability (140.4 mAh g-1 at 5 C rate). Therefore, the electronic conductivity and electrochemical performance of the FeF3·0.33H2O cathode material modified with CNTs and graphene composite conductive network can be effectively improved.

Enhancement of the electrochemical performance of the spinel structure LiNi0.5-xGaxMn1.5O4 cathode material by Ga doping.

A sol-gel method was adopted to obtain LiNi0.5-xGaxMn1.5O4 (x = 0, 0.04, 0.06, 0.08, 0.1) samples. The effect of Ga doping on LiNi0.5Mn1.5O4 and its optimum content were investigated, and the electrochemical properties at room temperature and at a high temperature were discussed. The structural, morphological, and vibrational features of LiNi0.5-xGaxMn1.5O4 (x = 0, 0.04, 0.06, 0.08, 0.1) compounds were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FT-IR). The XRD results demonstrate that all samples have a disordered spinel structure with a space group of Fd3m, and Ga doping restrains the formation of the LixNi1-xO secondary phase. FT-IR analysis reveals that Ga doping increases the degree of cation disorder. The SEM results reveal that all samples possess a fine spinel octahedron crystal. The electrochemical performance of the samples was investigated by galvanostatic charge/discharge tests, dQ/dV plots, and electrochemical impedance spectroscopy (EIS). The LiNi0.44Ga0.06Mn1.5O4 sample with the optimum content shows a superior rate performance and cycle stability after Ga doping, especially at a high discharge rate and high temperature. In addition, the LiNi0.44Ga0.06Mn1.5O4 sample retained 98.3% of its initial capacity of 115.7 mAhg-1 at the 3 C discharge rate after 100 cycles, whereas the pristine sample delivered a discharge capacity of 87.3 mAhg-1 at 3 C with a capacity retention of 80% at the 100th cycle. Compared with the pristine material, the LiNi0.44Ga0.06Mn1.5O4 sample showed a high capacity retention from 74 to 98.4% after 50 cycles at a 1 C discharge rate and 55 °C.

Synthesis of Spherical Silver-coated Li4Ti5O12 Anode Material by a Sol-Gel-assisted Hydrothermal Method.

ᅟ: Ag-coated spherical Li4Ti5O12 composite was successfully synthesized via a sol-gel-assisted hydrothermal method using an ethylene glycol and silver nitrate mixture as the precursor, and the influence of the Ag coating contents on the electrochemical properties of its was extensively investigated. X-ray diffraction (XRD) analysis indicated that the Ag coating does not change the spinel structure of Li4Ti5O12. The electrochemical impedance spectroscopy (EIS) analyses demonstrated that the excellent electrical conductivity of the Li4Ti5O12/Ag resulted from the presence of the highly conducting silver coating layer. Additionally, the nano-thick silver layer, which was uniformly coated on the particles, significantly improved this material's rate capability. As a consequence, the silver-coated micron-sized spherial Li4Ti5O12 exhibited excellent electrochemical performance. Thus, with an appropriate silver content of 5 wt.%, the Li4Ti5O12/Ag delivered the highest capacity of 186.34 mAh g-1 at 0.5C, which is higher than that of other samples, and maintained 92.69% of its initial capacity at 5C after 100 cycles. Even at 10C after 100 cycles, it still had a capacity retention of 89.17%, demonstrating remarkable cycling stability. TRIAL REGISTRATION: ISRCTN NARL-D-17-00568.

Synthesis and Electrochemical Properties of LiNi0.5Mn1.5O4 Cathode Materials with Cr3+ and F- Composite Doping for Lithium-Ion Batteries.

A Cr3+ and F- composite-doped LiNi0.5Mn1.5O4 cathode material was synthesized by the solid-state method, and the influence of the doping amount on the material's physical and electrochemical properties was investigated. The structure and morphology of the cathode material were characterized by XRD, SEM, TEM, and HRTEM, and the results revealed that the sample exhibited clear spinel features. No Cr3+ and F- impurity phases were found, and the spinel structure became more stable. The results of the charge/discharge tests, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) test results suggested that LiCr0.05Ni0.475Mn1.475O3.95F0.05 in which the Cr3+ and F- doping amounts were both 0.05, had the optimal electrochemical properties, with discharge rates of 0.1, 0.5, 2, 5, and 10 C and specific capacities of 134.18, 128.70, 123.62, 119.63, and 97.68 mAh g-1 , respectively. After 50 cycles at a rate of 2 C, LiCr0.05Ni0.475Mn1.475O3.95F0.05 showed extremely good cycling performance, with a discharge specific capacity of 121.02 mAh g-1 and a capacity retention rate of 97.9%. EIS test revealed that the doping clearly decreased the charge-transfer resistance.