title: RSK activation via ERK modulates human colon cancer cells response to PTHrP.
abstract: Parathyroid hormone-related peptide (PTHrP) is associated with several human cancers such as colon carcinoma. This disease is a complex multistep process that involves enhanced cell cycle progression and migration. Recently we obtained evidence that in the human colorectal adenocarcinoma Caco2 cells, exogenous PTHrP increases the proliferation and positively modulates cell cycle progression via ERK1/2, p38 MAPK and PI3K. The purpose of this study was to explore if the serine/threonine kinase RSK, which is involved in the progress of many cancers and it is emerging as a potential therapeutic target, mediates PTHrP effects on cancer colon cells. Western blot analysis revealed that PTHrP increases RSK phosphorylation via ERK1/2 signaling pathway but not through p38 MAPK. By performing subcellular fractionation, we found that the peptide also induces the nuclear localization of activated RSK, where many of its substrates are located. RSK participates in cell proliferation, in the upregulation of cyclin D1 and CDK6 and in the downregulation of p53 induced by PTHrP. Wound healing and transwell filter assays revealed that cell migration increased after PTHrP treatment. In addition, the hormone increases the protein expression of the focal adhesion kinase FAK, a regulator of cell motility. We observed that PTHrP induces cell migration and modulates FAK protein expression through ERK/RSK signaling pathway but not via p38 MAPK pathway. Finally,in vivostudies revealed that the hormone activates RSK in xenografts tumor. Taken together, our findings provide new insights into the deregulated cell cycle and migration that is characteristic of tumor intestinal cells.
authors.affiliation: Departamento de BiologíaBioquímica y Farmacia, INBIOSUR, Universidad Nacional del Sur (UNS) - CONICET, Bahía Blanca, Argentina.
authors.forename: Natalia
authors.initials: N
authors.lastname: Calvo
authors.affiliation: Departamento de BiologíaBioquímica y Farmacia, INBIOSUR, Universidad Nacional del Sur (UNS) - CONICET, Bahía Blanca, Argentina.
authors.forename: Pedro
authors.initials: P
authors.lastname: Carriere
authors.affiliation: Departamento de BiologíaBioquímica y Farmacia, INBIOSUR, Universidad Nacional del Sur (UNS) - CONICET, Bahía Blanca, Argentina.
authors.forename: María Julia
authors.initials: MJ
authors.lastname: Martin
authors.affiliation: Departamento de BiologíaBioquímica y Farmacia, INBIOSUR, Universidad Nacional del Sur (UNS) - CONICET, Bahía Blanca, Argentina cgentili@criba.edu.ar.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gentili
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D015552:Injections, Intralesional; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D019938:Cyclin D1; D051361:Cyclin-Dependent Kinase 6; D051417:Focal Adhesion Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D044162:Parathyroid Hormone-Related Protein; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; C530104:CCND1 protein, human; C496051:Ptk2 protein, mouse; C495911:CDK6 protein, human; C535148:Mapk1 protein, mouse
keywords: ERK1/2-p38MAPK; PTHrP; RSK; cell cycle migration; colon cancer cells