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| 2. |
- Beyer, Sarah, 1982-, et al.
(author)
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Fluorescent Molecularly Imprinted Polymer Layers against Sialic Acid on Silica-Coated Polystyrene Cores — Assessment of the Binding Behavior to Cancer Cells
- 2022
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In: Cancers. - : MDPI. - 2072-6694. ; 14:8
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Journal article (peer-reviewed)abstract
- Sialic acid (SA) is a monosaccharide usually linked to the terminus of glycan chains on the cell surface. It plays a crucial role in many biological processes, and hypersialylation is a common feature in cancer. Lectins are widely used to analyze the cell surface expression of SA. However, these protein molecules are usually expensive and easily denatured, which calls for the development of alternative glycan-specific receptors and cell imaging technologies. In this study, SA-imprinted fluorescent core-shell molecularly imprinted polymer particles (SA-MIPs) were employed to recognize SA on the cell surface of cancer cell lines. The SA-MIPs improved suspensibility and scattering properties compared with previously used core-shell SA-MIPs. Although SA-imprinting was performed using SA without preference for the α2,3-and α2,6-SA forms, we screened the cancer cell lines analyzed using the lectins Maackia Amurensis Lectin I (MAL I, α2,3-SA) and Sambucus Nigra Lectin (SNA, α2,6-SA). Our results show that the selected cancer cell lines in this study presented a varied binding behavior with the SA-MIPs. The binding pattern of the lectins was also demonstrated. Moreover, two different pentavalent SA conjugates were used to inhibit the binding of the SA-MIPs to breast, skin, and lung cancer cell lines, demonstrating the specificity of the SA-MIPs in both flow cytometry and confocal fluorescence microscopy. We concluded that the synthesized SA-MIPs might be a powerful future tool in the diagnostic analysis of various cancer cells.
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| 3. |
- Semenas, Julius, et al.
(author)
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The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer
- 2014
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:35, s. E3689-E3698
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Journal article (peer-reviewed)abstract
- Nitrogen-containing heterocyclic compounds are an important class of molecules that are commonly used for the synthesis of candidate drugs. Phosphatidylinositol-4-phosphate 5-kinase-α (PIP5Kα) is a lipid kinase, similar to PI3K. However, the role of PIP5K1α in oncogenic processes and the development of inhibitors that selectively target PIP5K1α have not been reported. In the present study we report that overexpression of PIP5K1α is associated with poor prognosis in prostate cancer and correlates with an elevated level of the androgen receptor. Overexpression of PIP5K1α in PNT1A nonmalignant cells results in an increased AKT activity and an increased survival, as well as invasive malignant phenotype, whereas siRNA-mediated knockdown of PIP5K1α in aggressive PC-3 cells leads to a reduced AKT activity and an inhibition in tumor growth in xenograft mice. We further report a previously unidentified role for PIP5K1α as a druggable target for our newly developed compound ISA-2011B using a high-throughput KINOMEscan platform. ISA-2011B was discovered during our synthetic studies of C-1 indol-3-yl substituted 1,2,3,4-tetrahydroisoquinolines via a Pictet-Spengler approach. ISA-2011B significantly inhibits growth of tumor cells in xenograft mice, and we show that this is mediated by targeting PIP5K1α-associated PI3K/AKT and the downstream survival, proliferation, and invasion pathways. Further, siRNA-mediated knockdown of PIP5K1α exerts similar effects on PC3 cells as ISA-2011B treatment, significantly inhibiting AKT activity, increasing apoptosis and reducing invasion. Thus, PIP5K1α has high potential as a drug target, and compound ISA-2011B is interesting for further development of targeted cancer therapy.
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- Syed Khaja, Azharuddin Sajid, et al.
(author)
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Cyclin A1 modulates the expression of vascular endothelial growth factor and promotes hormone-dependent growth and angiogenesis of breast cancer.
- 2013
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Journal article (peer-reviewed)abstract
- Alterations in cellular pathways related to both endocrine and vascular endothelial growth factors (VEGF) may contribute to breast cancer progression. Inhibition of the elevated levels of these pathways is associated with clinical benefits. However, molecular mechanisms by which endocrine-related pathways and VEGF signalling cooperatively promote breast cancer progression remain poorly understood. In the present study, we show that the A-type cyclin, cyclin A1, known for its important role in the initiation of leukemia and prostate cancer metastasis, is highly expressed in primary breast cancer specimens and metastatic lesions, in contrasting to its barely detectable expression in normal human breast tissues. There is a statistically significant correlation between cyclin A1 and VEGF expression in breast cancer specimens from two patient cohorts (p<0.01). Induction of cyclin A1 overexpression in breast cancer cell line MCF-7 results in an enhanced invasiveness and a concomitant increase in VEGF expression. In addition, there is a formation of protein-protein complexes between cyclin A1 and estrogen receptor ER-α cyclin A1 overexpression increases ER-α expression in MCF-7 and T47D cells. In mouse tumor xenograft models in which mice were implanted with MCF-7 cells that overexpressed cyclin A1 or control vector, cyclin A1 overexpression results in an increase in tumor growth and angiogenesis, which is coincident with an enhanced expression of VEGF, VEGFR1 and ER-α Our findings unravel a novel role for cyclin A1 in growth and progression of breast cancer, and suggest that multiple cellular pathways, including cell cycle regulators, angiogenesis and estrogen receptor signalling, may cooperatively contribute to breast cancer progression.
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| 6. |
- Wegiel, Barbara, et al.
(author)
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Multiple cellular mechanisms related to cyclin A1 in prostate cancer invasion and metastasis
- 2008
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In: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:14, s. 1022-1036
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Journal article (peer-reviewed)abstract
- BACKGROUND: Cyclin A1 is a cell cycle regulator that has been implicated in the progression of prostate cancer. Its role in invasion and metastasis of this disease has not been characterized.METHODS: Immunohistochemistry and cDNA microarray analyses were used to assess protein and mRNA expression of cyclin A1 and proteins with roles in metastasis, including vascular endothelial growth factor (VEGF), metalloproteinase 2 (MMP2), and MMP9, in human prostate cancer. Transient transfection and infection with viral vectors expressing cyclin A1 and short hairpin RNA (shRNA) targeting cyclin A1 were used to study the effects of altered cyclin A1 expression in PC3 prostate cancer cells. The BrdU assay, annexin V staining, and invasion chambers were used to examine cyclin A1 effects on proliferation, apoptosis, and invasion, respectively. The role of cyclin A1 and androgen receptor (AR) in transcription of VEGF and MMP2 was assessed by promoter mutation and chromatin immunoprecipitation. The effect of cyclin A1 expression on tumor growth and metastasis was analyzed in a mouse model of metastasis. All statistical tests were two-sided.RESULTS: Cyclin A1 protein and mRNA expression were statistically significantly higher in prostate cancers than in adjacent benign tissues. A statistically significant correlation between expression of cyclin A1 and of MMP2, MMP9, and VEGF was observed in prostate tumors from 482 patients (P values from Spearman rank correlation tests < .001). PC3 cells that overexpressed cyclin A1 showed increased invasiveness, and inhibition of cyclin A1 expression via shRNA expression reduced invasiveness of these cells. Eight of 10 mice (80%) bearing PC3 cells overexpressing cyclin A1 had infiltration of tumor cells in lymph node, liver, and lung, but all 10 mice bearing tumors expressing control vector were free of liver and lung metastases and only one mouse from this group had lymph node metastasis (P values from Fisher exact tests < .001). Cyclin A1, in concert with AR, bound to and increased expression from the VEGF and MMP2 promoters.CONCLUSIONS: Cyclin A1 contributes to prostate cancer invasion by modulating the expression of MMPs and VEGF and by interacting with AR.
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