title: MEK2 controls the activation of MKK3/MKK6-p38 axis involved in the MDA-MB-231 breast cancer cell survival: Correlation with cyclin D1 expression.
abstract: The Ras-Raf-MEK-ERK1/2 signaling pathway regulates fundamental processes in malignant cells. However, the exact contributions of MEK1 and MEK2 to the development of cancer remain to be established. We studied the effects of MEK small-molecule inhibitors (PD98059 and U0126) and MEK1 and MEK2 knock-down on cell proliferation, apoptosis and MAPK activation. We showed a diminution of cell viability that was associated with a downregulation of cyclin D1 expression and an increase of apoptosis marker in MEK2 silenced cells; by contrast, a slight increase of cell survival was observed in the absence of MEK1 that correlated with an augment of cyclin D1 expression. These data indicate that MEK2 but not MEK1 is essential for MDA-MB-231 cell survival. Importantly, the role of MEK2 in cell survival appeared independent on ERK1/2 phosphorylation since its absence did not alter the level of activated ERK1/2. Indeed, we have reported an unrevealed link between MEK2 and MKK3/MKK6-p38 MAPK axis where MEK2 was essential for the phosphorylation of MKK3/MKK6 and p38 MAPK that directly impacted on cyclin D1 expression. Importantly, the MEK1 inhibitor PD98059, like MEK1 silencing, induced an augment of cyclin D1 expression that correlated with an increase of MDA-MB-231 cell proliferation suggesting that MEK1 may play a regulatory role in these cells. In sum, the crucial role of MEK2 in MDA-MB-231 cell viability and the unknown relationship between MEK2 and MKK3/MKK6-p38 axis here revealed may open new therapeutic strategies for aggressive breast cancer.
authors.affiliation: Departamento de Morfologia, Universidade Federal de Minas Gerais, 31270-910 Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Huth
authors.affiliation: Departamento de Microbiologia, Universidade Federal de Minas Gerais, 31270-910 Belo Horizonte, Minas Gerais, Brazil; Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Jonas D
authors.initials: JD
authors.lastname: Albarnaz
authors.affiliation: Departamento de Microbiologia, Universidade Federal de Minas Gerais, 31270-910 Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Alice A
authors.initials: AA
authors.lastname: Torres
authors.affiliation: Departamento de Microbiologia, Universidade Federal de Minas Gerais, 31270-910 Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Bonjardim
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, 31270-910 Belo Horizonte, Minas Gerais, Brazil. Electronic address: ropertcatherine@gmail.com.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ropert
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D048371:MAP Kinase Kinase 3 / Q000378:metabolism*; D048669:MAP Kinase Kinase 6 / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D002070:Butadienes; C530104:CCND1 protein, human; D005419:Flavonoids; D009570:Nitriles; C113580:U 0126; D019938:Cyclin D1; C482128:MAP2K2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D048370:MAP Kinase Kinase 2; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Breast cancer; Cyclin D1; MDA-MB-231; MEK2; MEKK3/MKK6; p38