title: PTEN Overexpression Cooperates With Lithium to Reduce the Malignancy and to Increase Cell Death by Apoptosis via PI3K/Akt Suppression in Colorectal Cancer Cells.
abstract: 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.
authors.affiliation: Grupo de Biologia Estrutural, Divisão de Biologia Celular, Centro de Pesquisas, Instituto Nacional de Câncer, Rua André Cavalcanti, 37, 5andar, Rio de Janeiro, Brasil.
authors.forename: Wallace Martins
authors.initials: WM
authors.lastname: de Araujo
authors.affiliation: Departamento de Ciências Básicas, Campus Universitário de Nova Friburgo, Universidade Federal Fluminense, UFF, Nova Friburgo, Rio de Janeiro, Brasil.
authors.forename: Bruno Kaufmann
authors.initials: BK
authors.lastname: Robbs
authors.affiliation: Grupo de Biologia Estrutural, Divisão de Biologia Celular, Centro de Pesquisas, Instituto Nacional de Câncer, Rua André Cavalcanti, 37, 5andar, Rio de Janeiro, Brasil.
authors.forename: Lilian G
authors.initials: LG
authors.lastname: Bastos
authors.affiliation: Grupo de Biologia Estrutural, Divisão de Biologia Celular, Centro de Pesquisas, Instituto Nacional de Câncer, Rua André Cavalcanti, 37, 5andar, Rio de Janeiro, Brasil.
authors.forename: Waldemir F
authors.initials: WF
authors.lastname: de Souza
authors.affiliation: Banco de Tumores e DNA do Maranhão, Universidade Federal do Maranhão, Rua Coelho Neto, 311, São Luís, MA, Brasil.
authors.forename: Flávia C B
authors.initials: FC
authors.lastname: Vidal
authors.affiliation: Grupo de Regulação Gênica, Programa de Biologia Celular, Centro de Pesquisas, Instituto Nacional de Câncer, Rua André Cavalcanti, 37, 5andar, Rio de Janeiro, Brasil.
authors.forename: João P B
authors.initials: JP
authors.lastname: Viola
authors.affiliation: Grupo de Biologia Estrutural, Divisão de Biologia Celular, Centro de Pesquisas, Instituto Nacional de Câncer, Rua André Cavalcanti, 37, 5andar, Rio de Janeiro, Brasil.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Morgado-Diaz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018021:Lithium Chloride
keywords: COLORECTAL CANCER; LITHIUM; PI3K/Akt; PTEN