title: Glaucarubinone inhibits colorectal cancer growth by suppression of hypoxia-inducible factor 1α and β-catenin via a p-21 activated kinase 1-dependent pathway.
abstract: p-21-Activated kinase 1 (PAK1) enhances colorectal cancer (CRC) progression by stimulating Wnt/β-catenin, ERK and AKT pathways. PAK1 also promotes CRC survival via up-regulation of hypoxia-inducible factor 1α (HIF-1α), a key player in cancer survival. Glaucarubinone, a quassinoid natural product, inhibits pancreatic cancer growth by down-regulation of PAK1. The aim of this study was to investigate the effect of glaucarubinone on CRC growth and metastasis, and the mechanism involved. Cell proliferation was measured in vitro by [(3)H]-thymidine incorporation and in vivo by volume of tumor xenografts. Protein concentrations were measured by Western blotting of cell extracts. We report here that glaucarubinone inhibited CRC growth both in vitro and in vivo. The potency of glaucarubinone as an inhibitor of cell proliferation was negatively correlated to PAK1 expression in CRC cells. Glaucarubinone suppressed the expression of HIF-1α and β-catenin. Knockdown of PAK1 by shRNA enhanced inhibition by glaucarubinone while constitutively active PAK1 blocked the inhibitory effect. Our findings indicate that glaucarubinone inhibited CRC growth by down-regulation of HIF-1α and β-catenin via a PAK1-dependent pathway.
authors.affiliation: Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria 3084, Australia.
authors.forename: Nhi
authors.initials: N
authors.lastname: Huynh
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Beutler
authors.affiliation: Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria 3084, Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Shulkes
authors.affiliation: Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria 3084, Australia.
authors.forename: Graham S
authors.initials: GS
authors.lastname: Baldwin
authors.affiliation: Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria 3084, Australia. Electronic address: hong.he@unimelb.edu.au.
authors.forename: Hong
authors.initials: H
authors.lastname: He
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005900:Glaucarubin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000037:antagonists & inhibitors*; D054462:p21-Activated Kinases / Q000502:physiology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051176:beta Catenin; C015235:glaucarubinone; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D005900:Glaucarubin
keywords: CRC; Glaucarubinone; HIF-1α; PAK1; β-Catenin