title: LPA Induces Colon Cancer Cell Proliferation through a Cooperation between the ROCK and STAT-3 Pathways.
abstract: Lysophosphatidic acid (LPA) plays a critical role in the proliferation and migration of colon cancer cells; however, the downstream signaling events underlying these processes remain poorly characterized. The aim of this study was to investigate the signaling pathways triggered by LPA to regulate the mechanisms involved in the progression of colorectal cancer (CRC). We have used three cell line models of CRC, and initially analyzed the expression profile of LPA receptors (LPAR). Then, we treated the cells with LPA and events related to their tumorigenic potential, such as migration, invasion, anchorage-independent growth, proliferation as well as apoptosis and cell cycle were evaluated. We used the Chip array technique to analyze the global gene expression profiling that occurs after LPA treatment, and we identified cell signaling pathways related to the cell cycle. The inhibition of these pathways verified the conclusions of the transcriptomic analysis. We found that the cell lines expressed LPAR1, -2 and -3 in a differential manner and that 10 μM LPA did not affect cell migration, invasion and anchorage-independent growth, but it did induce proliferation and cell cycle progression in HCT-116 cells. Although LPA in this concentration did not induce transcriptional activity of β-catenin, it promoted the activation of Rho and STAT-3. Moreover, ROCK and STAT-3 inhibitors prevented LPA-induced proliferation, but ROCK inhibition did not prevent STAT-3 activation. Finally, we observed that LPA regulates the expression of genes related to the cell cycle and that the combined inhibition of ROCK and STAT-3 prevented cell cycle progression and increased the LPA-induced expression of cyclins E1, A2 and B1 to a greater degree than either inhibitor alone. Overall, these results demonstrate that LPA increases the proliferative potential of colon adenocarcinoma HCT-116 cells through a mechanism involving cooperation between the Rho-ROCK and STAT3 pathways involved in cell cycle control.
authors.affiliation: Diretoria de Metrologia Aplicada às Ciências da Vida-Dimav, Instituto Nacional de Metrologia, Qualidade e Tecnologia-INMETRO, Xerém, Duque de Caxias, RJ, Brasil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Leve
authors.affiliation: Grupo de Biologia Estrutural, Divisão de Biologia Celular, Centro de Pesquisas, Instituto Nacional de Câncer-INCA, Rio de Janeiro, RJ, Brasil.
authors.forename: Rubem J
authors.initials: RJ
authors.lastname: Peres-Moreira
authors.affiliation: Centro de Transplante de Medula Óssea (CEMO), Instituto Nacional de Câncer-INCA, Rio de Janeiro, RJ, Brasil.
authors.forename: Renata
authors.initials: R
authors.lastname: Binato
authors.affiliation: Centro de Transplante de Medula Óssea (CEMO), Instituto Nacional de Câncer-INCA, Rio de Janeiro, RJ, Brasil.
authors.forename: Eliana
authors.initials: E
authors.lastname: Abdelhay
authors.affiliation: Grupo de Biologia Estrutural, Divisão de Biologia Celular, Centro de Pesquisas, Instituto Nacional de Câncer-INCA, Rio de Janeiro, RJ, Brasil.
authors.forename: José A
authors.initials: JA
authors.lastname: Morgado-Díaz
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014945:Wound Healing; D051176:beta Catenin / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051176:beta Catenin; D054460:rho-Associated Kinases; C032881:lysophosphatidic acid