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

• Published in: Journal of cancer research and clinical oncology 2010-11, Vol.136 (11), p.1773-1782
• Main Authors: de Araújo, Wallace Martins, Vidal, Flavia Castello Branco, de Souza, Waldemir Fernandes, de Freitas Junior, Julio César Madureira, de Souza, Wanderley, Morgado-Diaz, Jose Andres
• Format: Article
• Language: English
• Subjects: Alkaline Phosphatase - antagonists & inhibitors; Antineoplastic agents; Apical junctional complex; beta Catenin - metabolism; Biological and medical sciences; Cadherins - metabolism; Cancer Research; cell differentiation; Cell Division - drug effects; Cell Line, Tumor; Chromones - therapeutic use; Colony-Forming Units Assay; colorectal neoplasms; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Enzyme Inhibitors - therapeutic use; Gastroenterology. Liver. Pancreas. Abdomen; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; GSK-3β; Hematology; Humans; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Morpholines - therapeutic use; Oncology; Original Paper; Pharmacology. Drug treatments; Phenotype; PI3K/Akt pathway; Proto-Oncogene Proteins c-akt - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Wnt/β-catenin pathway; Wound Healing - drug effects
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-010-0836-5

Purpose During 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. Methods HCT-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. Results PI3K 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. Conclusion Our 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.