Flávia Castello Branco Vidal

Lithium reduces tumorigenic potential in response to EGF signaling in human colorectal cancer cells.

Lithium is a specific inhibitor of GSK3-β, and hence, an activator of the Wnt/β-catenin pathway, whereas the epidermal growth factor (EGF) has been linked to malignant transformation in epithelial cancer cells. Both pathways are aberrantly activated in most colorectal cancers (CRCs). However, the relationship between them in modulating events related to the progression of this cancer type remains to be defined. In this study, we investigated whether the Wnt/β-catenin and EGFR pathways converge to modulate the malignant potential of CRC. We used Caco-2 cells, a well-established model used to study CRC, and treatments with lithium chloride, as a modulator of the Wnt/β-catenin pathway, and with EGF as an inducer of EGFR signaling. We found that both agents altered the subcellular distribution of claudin-1 and β-catenin, two important proteins of the apical junctional complex, but not their abundance in the cell. Nuclear stabilization of β-catenin, a marker of Wnt pathway activation, was observed after treatment with both compounds. However, lithium, but not EGF, inhibited GSK3-β, indicating that these agents modulate this enzyme in a differential fashion. Furthermore, EGF treatment increased the proliferative and migratory capacity but did not alter the colony formation potential of these cells. Surprisingly, lithium, known to activate the Wnt/β-catenin pathway, inhibited the increased proliferation by arresting cells in the G2/M phase as well as the cell migration promoted by EGF, as demonstrated by the combined treatment with these agents. Lithium treatment alone reduced the cell colony formation. Thus, our findings suggest that lithium plays an important role in regulating cellular events related to tumor progression in CRC.

PI3K/Akt and GSK-3β prevents in a differential fashion the malignant phenotype of colorectal cancer cells

PurposeDuring colorectal cancer progression, the loss of differentiation and cell–cell adhesion as well as a higher migratory potential are well-defined features; however, the signaling mechanism governing these events is not fully elucidated. The aim of this study was to investigate the role that PI3K and downstream effectors play in controlling colon cancer malignant phenotypes.MethodsHCT-116 cells, a human model of colon cancer, which are highly metastatic and undifferentiated, were treated with LY294002, a specific inhibitor of PI3K. Cell differentiation and apical junctional complex (AJC) formation were monitored using alkaline phosphatase and electron microscopy analysis. Immunofluorescence and Western blotting were used to accompany the subcellular localization of AJC proteins. PI3K downstream molecules were analyzed by western blotting, and proliferation, wound healing, and colony formation techniques to determine malignant phenotype alterations.ResultsPI3K inhibition increased alkaline phosphatase activity, led to an enterocyte-like growth and formed a functional AJC. LY294002 treatment was able to recruit E-cadherin, β-catenin, claudin-3, and ZO-1 to the cell–cell contact region, and this effect was essential for AJC assembly and association of these proteins to the cytoskeleton. Furthermore, we provided evidence that PI3K inhibition leads to a decrease in p-Akt and p-GSK-3β and increased p-β-catenin levels, which in turn controlled cell proliferation, motility, and colony formation.ConclusionOur results demonstrate that PI3K/Akt and GSK-3β prevents in a differential fashion the malignant phenotype of HCT-116 colorectal cancer cells, which could constitute a potential therapeutic target for treatment of this cancer type.

PTEN Overexpression Cooperates With Lithium to Reduce the Malignancy and to Increase Cell Death by Apoptosis via PI3K/Akt Suppression in Colorectal Cancer Cells

Lithium is a well‐established non‐competitive inhibitor of glycogen synthase kinase‐3β (GSK‐3β), a kinase that is involved in several cellular processes related to cancer progression. GSK‐3β is regulated upstream by PI3K/Akt, which is negatively modulated by PTEN. The role that lithium plays in cancer is controversial because lithium can activate or inhibit survival signaling pathways depending on the cell type. In this study, we analyzed the mechanisms by which lithium can modulate events related to colorectal cancer (CRC) progression and evaluated the role that survival signaling pathways such as PI3K/Akt and PTEN play in this context. We show that the administration of lithium decreased the proliferative potential of CRC cells in a GSK‐3β‐independent manner but induced the accumulation of cells in G2/M phase. Furthermore, high doses of lithium increased apoptosis, which was accompanied by decreased proteins levels of Akt and PTEN. Then, cells that were induced to overexpress PTEN were treated with lithium; we observed that low doses of lithium strongly increased apoptosis. Additionally, PTEN overexpression reduced proliferation, but this effect was minor compared with that in cells treated with lithium alone. Furthermore, we demonstrated that PTEN overexpression and lithium treatment separately reduced cell migration, colony formation, and invasion, and these effects were enhanced when lithium treatment and PTEN overexpression were combined. In conclusion, our findings indicate that PTEN overexpression and lithium treatment cooperate to reduce the malignancy of CRC cells and highlight lithium and PTEN as potential candidates for studies to identify new therapeutic approaches for CRC treatment. J. Cell. Biochem. 117: 458–469, 2016.

Cytotoxic analysis and chemical characterization of fractions of the hydroalcoholic extract of the Euterpe oleracea Mart. seed in the MCF-7 cell line

To analyse the antineoplastic activity of fractions derived from the hydroalcoholic extract of Euterpe oleracea Mart. seed in the MCF‐7 cell line and to identify the compounds responsible for the antineoplastic action.

Osteoporosis in primary care: an opportunity to approach risk factors

INTRODUCTION Climacteric women are susceptible to a number of changes, among them osteoporosis. Osteoporosis is a disease characterized by low bone mass and susceptibility to fracture. Currently, this disease is a public health issue, being necessary to recognize its risk factors. OBJECTIVES Identify risk factors related to osteoporosis in women attending PROPIS/PROEX/UFMA, tracing a socio-demographic characterization and considering community lifestyles. MATERIAL AND METHODS This is a transversal retrospective clinical with a quantitative approach study conducted between March and June 2013 in São Luís-MA with 107 women treated at the Programa de Práticas de Integralidade em Saúde (PROPIS - Integrality Health Practice Program). The study was approved by the University Hospital Ethics Committee of UFMA under opinion no. 362/07. Data were tabulated and analyzed in the epidemiological Epi-Info(®) software, version 3.4.1. RESULTS The brown color was predominant, consensual relationships proved to be a protective factor and low education was a risk factor. The average age of the group with menopause was 54.1 years and without menopause was 31.3 years (p<0.0001). The average age of menopause was 43.7 years. The irregular menstrual cycle was a protective factor. The average number of pregnancies was 4.56 for the group with menopause and 2.45 for the group without menopause, with most births occurring normally (p<0.0001). Smoking, physical inactivity and caffeine intake were risk factors, while the absence of alcoholism and of soda intake were protective factors for the disease. CONCLUSION The patients followed the socioeconomic and demographic profile of Maranhão. Most had menarche and menopause in appropriate periods, showed no positive family history of osteoporosis, did not usually drink alcohol, were sedentary and the caffeine intake was high.