title: A Derivative of Differentiation-Inducing Factor-3 Inhibits PAK1 Activity and Breast Cancer Cell Proliferation.
abstract: Differentiation-inducing factors 1-3 (DIFs 1-3), chlorinated alkylphenones identified in the cellular slime moldDictyostelium discoideum,are considered anti-tumor agents because they inhibit proliferation of a variety of mammalian tumor cellsin vitro. Although the anti-proliferative effects of DIF-1 and DIF-3 are well-documented, the precise molecular mechanisms underlying the actions of DIFs have not been fully elucidated. In this study, we examined the effects of DIFs and their derivatives on PAK1, a key serine-threonine kinase, which is activated by multiple ligands and regulates cell proliferation. We examined the effect of DIF derivatives on PAK1 kinase activity in cells. We also examined the effect of DIF-3(+1) derivative on PAK1 kinase activityin vitro, cyclin D1 promoter activity and breast cancer cell proliferation. It was found that some derivatives strongly inhibited PAK1 kinase activity in human breast cancer MCF-7 cells stably over expressing PAK1. Among the derivatives, DIF-3(+1) was most potent, which directly inhibited kinase activity of recombinant purified PAK1 in anin vitrokinase assay. Furthermore, DIF-3(+1) strongly inhibited both cyclin D1 promoter activity and proliferation of MCF-7 and T47D breast cancer cells stably over expressing PAK1 in response to prolactin, estrogen, epidermal growth factor and heregulin. In the present study we propose PAK1 as DIF-3(+1) target mediating its anti-proliferative effect.
authors.affiliation: The Department of Biological Sciences, University of Toledo, Ohio, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Oladimeji
authors.affiliation: Institute for Molecular & Cellular Regulation, Gunma University, Maebashi, Japan ; Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan.
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kubohara
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Oshima
authors.affiliation: The Department of Biological Sciences, University of Toledo, Ohio, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Rusch
authors.affiliation: The Department of Biological Sciences, University of Toledo, Ohio, USA.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Skerl
authors.affiliation: The Department of Biological Sciences, University of Toledo, Ohio, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Diakonova
keywords: Breast cancer; Cell proliferation; Cyclin D; Differentiation-inducing factor-3; PAK1 kinase