title: Suppression of phospho-p85α-GTP-Rac1 lipid raft interaction by bichalcone analog attenuates cancer cell invasion.
abstract: The p85α subunit of phosphatidylinositol 3-kinase (PI3K) acts as a key regulator of cell proliferation and motility, which mediates signals that confer chemoresistance to many human cancer cells. Using small interfering RNAs against matrix metalloproteinase-2 (MMP-2) and the MMP-2 promoter-driven luciferase assay, we showed that the new synthetic bichalcone analog TSWU-CD4 inhibits the invasion of human cancer cells by down-regulating MMP-2 expression. Treatment with TSWU-CD4 inhibited MMP-2 expression and cell invasion, which were restored by ectopic wild type (wt) p85α or a constitutively active form of MAPK kinase 3 (CA MKK3), CA MKK6, or CA p38α mitogen-activated protein kinase (MAPK). The attenuated formation of lipid raft-associated phospho (p)-p85α-GTP-Rac1 complexes, protein kinase B (Akt) Ser 473 phosphorylation, and cell invasion by TSWU-CD4 was reversed by overexpression of wt p85α or the p85α Brc-homology (BH) domain. The ectopic expression of CA Rac1L61(but not wt Rac1) could overcome the suppression of Ser 473 phosphorylation, lipid raft association of Akt, the interaction between GTP-bound Rac1 and p85α in lipid rafts, and cell invasion by TSWU-CD4. The involvement of Akt activity in the functions of NF-κB-mediated MMP-2 was further confirmed through the attenuation of Akt phosphorylation signaling using the Akt-specific inhibitor MK-2206 and ectopic expression of NF-κB p65. Collectively, the inhibitory effect of TSWU-CD4 on cancer cell invasion was likely to suppress the p-p85α-GTP-Rac1 interaction in lipid rafts by targeting the p85α BH domain, which resulted in the suppression of MMP-2 expression via the PI3K-Akt-mediated ERK-MKK3/MKK6-p38 MAPK-NF-κB signaling pathway. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Laboratory, Armed Force Taichung General Hospital, Taichung, Taiwan.
authors.forename: Hui-Li
authors.initials: HL
authors.lastname: Lu
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan.
authors.forename: Shih-Shun
authors.initials: SS
authors.lastname: Chen
authors.affiliation: Division of Laboratory, Armed Force Taichung General Hospital, Taichung, Taiwan.
authors.forename: Wen-Tung
authors.initials: WT
authors.lastname: Hsu
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan.
authors.forename: Yao-Cheng
authors.initials: YC
authors.lastname: Lu
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan.
authors.forename: Chuan-Chun
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Department of Chemistry, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
authors.forename: Meng-Liang
authors.initials: ML
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D015536:Down-Regulation; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D021962:Membrane Microdomains / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000517:prevention & control*; D010879:Piperazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D047188:Chalcones; D016328:NF-kappa B; D010879:Piperazines; C107953:RAC1 protein, human; C000600957:TSWU-CD4 compound; D006160:Guanosine Triphosphate; D058543:Class Ia Phosphatidylinositol 3-Kinase; D020778:Matrix Metalloproteinase 2; D020830:rac1 GTP-Binding Protein
keywords: MMP-2; Rac1; bichalcone analog TSWU-CD4; invasion; p85α