title: Src is a novel potential off-target of RXR agonists, 9-cis-UAB30 and Targretin, in human breast cancer cells.
abstract: 9-cis-UAB30 (UAB30) and Targretin are well-known retinoid X receptor (RXR) agonists. They were highly effective in decreasing the incidence of methylnitrosourea (MNU)-induced mammary cancers. However, whether the anti-mammary cancer effects of UAB30 or Targretin originate from the activation of RXR is unclear. In the present study, we hypothesized that UAB30 and Targretin not only affect RXR, but likely influence one or more off-target proteins. Virtual screening results suggest that Src is a potential target for UAB30 and Targretin that regulates extracellular matrix (ECM) molecules and cell motility and invasiveness. In vitro kinase assay data revealed that UAB30 or Targretin interacted with Src and attenuated its kinase activity. We found that UAB30 or Targretin substantially inhibited invasiveness and migration of MCF-7 and SK-BR-3 human breast cancer cells. We examined the effects of UAB30 and Targretin on the expression of matrix metalloproteinases (MMP)-9, which are known to play an essential role in tumor invasion. We show that activity and expression of MMP-9 were decreased by UAB30 or Targretin. Western blot data showed that UAB30 or Targretin decreased AKT and its substrate molecule p70(s6k), which are downstream of Src in MCF-7 and SK-BR-3 cells. Moreover, knocking down the expression of Src effectively reduced the sensitivity of SK-BR-3 cells to the inhibitory effects of UAB30 and Targretin on invasiveness. Taken together, our results demonstrate that UAB30 and Targretin each inhibit invasion and migration by targeting Src in human breast cancer cells.
authors.affiliation: The Hormel Institute, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Mi-Sung
authors.initials: MS
authors.lastname: Kim
authors.affiliation: The Hormel Institute, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Lim
authors.affiliation: The Hormel Institute, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: The Hormel Institute, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Chemoprevention Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.affiliation: The Hormel Institute, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: The Hormel Institute, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
mesh_terms: D000077610:Bexarotene; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D009281:Naphthalenes / Q000494:pharmacology*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000517:prevention & control; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D047488:Retinoid X Receptors / Q000819:agonists*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D005231:Fatty Acids, Unsaturated; D009281:Naphthalenes; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene; D015688:Oncogene Protein pp60(v-src); D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020780:Matrix Metalloproteinase 9; C112106:UAB 30
keywords: 9-cis-UAB30; Src; Targretin; breast cancer cells; invasion and migration