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In our study, we explored how parasitic nematodes, specifically Heligmosomoides polygyrus, influence the immune response, focusing on their potential role in tumor growth. The study aimed to understand the mechanisms by which these parasites modify immune cell activation, particularly in macrophages, and how this might create an environment conducive to tumor growth. Our methods involved analyzing the effects of H. polygyrus excretory-secretory antigens on macrophage activation and their subsequent impact on breast cancer cell lines EMT6 and 4T1. We observed that these antigens significantly increased the expression of genes associated with both pro-inflammatory and anti-inflammatory molecules, such as inducible nitric oxide synthase, TNF-α, (Tumor Necrosis Factor) Il-6 (Interleukin), and arginase. Additionally, we observed changes in the expression of macrophage surface receptors like CD11b, F4/80, and TLR4 (Toll-like receptor 4). Our findings indicate that the antigens from H. polygyrus markedly alter macrophage behavior and increase the proliferation of breast cancer cells in a laboratory setting. This study contributes to a deeper understanding of the complex interactions between parasitic infections and cancer development, highlighting the need for further research in this area to develop potential new strategies for cancer treatment.

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As a recognized endocrine disruptor in the environment targeting estrogen receptors (ERs), Bisphenol A (BPA) and its bisphenol S (BPS) analogs are involved in the development of breast cancer. Epigenetic modifications are crucial in many biological processes, and DNA hydroxymethylation (DNAhm) coupled with histone methylation is implicated in epigenetic machinery covering cancer occurrence. Our previous study indicated that BPA/BPS induces breast cancer cell (BCC) proliferation with enhanced estrogenic transcriptional activity and causes the change of DNAhm depending on ten-eleven translocation 2 (TET2) dioxygenase. Herein, we investigated the interplay of KDM2A-mediated histone demethylation with ER-dependent estrogenic activity (EA) and identified their function in DNAhm catalyzed by TET2 for ER-positive (ER+) BCC proliferation induced by BPA/BPS. We found that BPA/BPS-treated ER+ BCCs presented increased KDM2A mRNA and protein levels but reduced TET2 and genomic DNAhm. Furthermore, KDM2A promoted H3K36me2 loss and suppressed TET2-dependent DNAhm by reducing its chromatin binding during BPA/BPS-induced cell proliferation. Results of Co-IP & ChIP assays suggested the direct interplay of KDM2A with ERα in multiple manners. KDM2A reduced the lysine methylation of ERα protein to increase its phosphorylated activation. On the other hand, ERα did not affect KDM2A expression, while KDM2A protein levels decreased after ERα deletion, indicating that ERα binding might maintain KDM2A protein stability. In conclusion, a potential feedback circuit of KDM2A/ERα-TET2-DNAhm was identified among ER+ BCCs with significant effects on regulating BPA/BPS-induced cell proliferation. These insights advanced the understanding of the relationship between histone methylation, DNAhm, and cancer cell proliferation with EA attributed to BPA/BPS exposure in the environment.

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Src kinase activity controls diverse cellular functions, including cell growth, migration, adhesion, and survival. It is de-regulated in several cancers, including breast cancer, where it is highly expressed and phosphorylated. Thus, targeting Src by a small molecule is a feasible strategy for managing different breast cancer types. Several Src kinase inhibitors are available, including the FDA-approved drug (dasatinib). However, they are primarily ATP-competitive inhibitors that have been reported to lack specificity towards Src. We have a long-time interest in discovering protein kinase inhibitors that are non-competitive for ATP. In this project, three groups of 2'-aminospiro[pyrano[3,2-c]quinoline]-3'-carbonitrile derivatives were designed and synthesized, hypothesizing that small molecules with a spiro scaffold appended to a pyrano[3,2-c]quinoline analog could act as non-ATP competitive Src kinase inhibitors. 3b, 3c, and 3d inhibited Src kinase activity with IC50s of 4.9, 5.9, and 0.9 µM, respectively. At the same time, they did not impact the MDM2/p53 interaction in HEK293 cells, which has been reported to be affected by some spirocyclic compounds. 25 µM of 3b, 3c, or 3d did not inhibit the kinase activity of ERK2, JNK1, or p38-alpha in an in-vitro kinase assay. Steady-state kinetic studies for the effect of 3d on the ability of recombinant Src to phosphorylate its substrate (Srctide) revealed a non-ATP competitive inhibition mechanism. 1.6 µM of 3d was enough to diminish Src, Fak, and paxillin phosphorylation in the breast cancer cell lines MDA-MB-231 and MCF7. In the NCI screening, 3d induced broad tumor cytotoxicity for the NCI-60 cell lines, including all the breast cancer cell lines. The potency of 3b, 3c, and 3d to inhibit migration, proliferation, and colony formation of MDA-MB-231 and proliferation of MCF7 cells correlates with their potency to suppress Src kinase activity in the same cell line. Noticeably, the cell growth suppression and apoptosis induction in the tested cell lines can be attributed to the ability of the new derivatives to suppress the ERK and Akt survival pathways downstream of Src.

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Phthalates comprise a group of synthetic chemicals present in the environment because of their wide use as plasticizers and as additives in products for personal care. Among others, diethyl phthalate (DEP) is largely used in products for infants, children, and adults, in which its exposure has been correlated with an increased risk of breast cancer. The adverse health outcomes deriving from phthalate exposure have been associated with their activity as endocrine disruptors (EDCs) of the steroid and thyroid hormone signaling by affecting developmental and reproductive health, and even carcinogenicity. However, the estrogen disruptor activities of DEP are still controversial, and the mechanism at the root of the estrogenic-disrupting action of DEP remains to be clarified. Here, we evaluated the DEP mechanism of action on the activation status of estrogen receptor α (ERα) by analyzing the receptor's phosphorylation as well as both nuclear and extra-nuclear pathways triggered by the receptor to modulate the proliferation of breast cancer cells. Although DEP does not bind to ERα, our results suggest that this phthalate ester exerts multiple parallel interactions with ERα signaling and emphasize the importance to determine an appropriate battery of in vitro methods that will include specific molecular mechanisms involved in the endocrine disruption.

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The purpose of this study was to explore the effect of Allograft Inflammatory Factor 1 (AIF-1) on the regulation of proliferation of breast cancer cells. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), cell culture and counting, and mass spectrometry were performed. The biologically active high-purity recombinant protein rhAIF-1 was obtained by optimizing the rhAIF-1 protein purification system, and MDA-MB-231 and MDA-MB-361 breast cancer cell lines were used. After adding to the culture medium, rhAIF-1 was found to promote cell proliferation in dose-dependent and time-dependent manners. The purified protein rhAIF-1 was marked with rhodamine and incubated with the cells. Confocal imaging analysis revealed that the foreign protein was localized in the cytoplasm, and rhAIF-1 was unevenly distributed in the cytoplasm. Although AIF-1 accumulates around the nucleus, it can not enter the nucleus, suggesting that other factors might be involved in the regulation of cell proliferation. In order to find the possible interacting protein of rhAIF-1, protein immunoprecipitation technique and mass spectrometry were employed, and it was indicated that ADAM28m was the possible interacting protein of rhAIF-1. The interaction between rhAIF-1 and ADAM28m was validated by immunoprecipitation along with Western blotting. It was found that rhAIF-1 could precipitate ADAM28m protein by immunoprecipitation. The results indicated that IF-1 participates in the development of breast cancer by interacting with ADAM28m and activating downstream signaling pathways. It was concluded that AIF-1 provides a new idea for the molecular mechanism of breast cancer cell proliferation and acts as a new target for the prevention and treatment of breast cancer in the future.

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The study was conducted in vitro with human breast cancer cells BCaP-37, to determine the effects of selenium, vitamin A, vitamin E and a combination of these three nutrients on cell proliferation and cellular nucleic acid content. Selenium as sodium selenite had two phases of effect on cancer cell proliferation: the low concentrations of selenium (less than 5 ?M) stimulated cell growth and increased the cellular nucleic acid content; the high concentrations (more than 5 ?M) depressed cell growth and reduced the cellular nucleic acid content with dose-dependence. Vitamin A acetate inhibited cancer cell growth significantly, but vitamin A acid inhibited to some extent, and was less effective than vitamin A acetate. Vitamin E had less inhibitory effect compared to vitamin A acetate and the inhibitory percentages were lower than 40% in all treatment groups. Combination of selenium (5 ?M) and vitamin E (20mg/L) or selenium and vitamin A acetate (2mg/L), no synergism for the reduction of the contents of cellular nucleic acids (DNA and RNA) were observed. The combination of selenium, vitamin A acetate and vitamin E at such levels reduced cellular DNA and RNA contents obviously; RNA content was significantly lower than any other treatment group and was reduced synergis-tically. It was indicated that the combination of selenium, vitamin A acetate, vitamin E was synergistic for inhibition of cell proliferation. Results also showed the reversible tendency in the inhibition of cell proliferation by combination of these three nutrients. It was suggested that combination of selenium, vitamin A and E might be benificial for the prevention and adjuvant treatment of human breast cancer.