title: Mitogen-activated protein kinase kinase 4 (MAP2K4) promotes human prostate cancer metastasis.
abstract: Prostate cancer (PCa) is the second leading cause of cancer death in the US. Death from PCa primarily results from metastasis. Mitogen-activated protein kinase kinase 4 (MAP2K4) is overexpressed in invasive PCa lesions in humans, and can be inhibited by small molecule therapeutics that demonstrate favorable activity in phase II studies. However, MAP2K4's role in regulating metastatic behavior is controversial and unknown. To investigate, we engineered human PCa cell lines which overexpress either wild type or constitutive active MAP2K4. Orthotopic implantation into mice demonstrated MAP2K4 increases formation of distant metastasis. Constitutive active MAP2K4, though not wild type, increases tumor size and circulating tumor cells in the blood and bone marrow. Complementary in vitro studies establish stable MAP2K4 overexpression promotes cell invasion, but does not affect cell growth or migration. MAP2K4 overexpression increases the expression of heat shock protein 27 (HSP27) protein and protease production, with the largest effect upon matrix metalloproteinase 2 (MMP-2), both in vitro and in mouse tumor samples. Further, MAP2K4-mediated increases in cell invasion are dependent upon heat shock protein 27 (HSP27) and MMP-2, but not upon MAP2K4's immediate downstream targets, p38 MAPK or JNK. We demonstrate that MAP2K4 increases human PCa metastasis, and prolonged over expression induces long term changes in cell signaling pathways leading to independence from p38 MAPK and JNK. These findings provide a mechanistic explanation for human studies linking increases in HSP27 and MMP-2 to progression to metastatic disease. MAP2K4 is validated as an important therapeutic target for inhibiting human PCa metastasis.
authors.affiliation: Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Pavese
authors.affiliation: Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ogden
authors.affiliation: Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Voll
authors.affiliation: Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Preventative Medicine, Northwestern University, Chicago, Illinois, United States of America; Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Borko
authors.initials: B
authors.lastname: Jovanovic
authors.affiliation: Department of Medicine, Northwestern University, Chicago, Illinois, United States of America; Department of Preventative Medicine, Northwestern University, Chicago, Illinois, United States of America; Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois, United States of America; Center for Molecular Innovation and Drug Discovery, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Bergan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D055551:HSP27 Heat-Shock Proteins; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse