title: CDK2 and mTOR are direct molecular targets of isoangustone A in the suppression of human prostate cancer cell growth.
abstract: Licorice extract which is used as a natural sweetener has been shown to possess inhibitory effects against prostate cancer, but the mechanisms responsible are poorly understood. Here, we report a compound, isoangustone A (IAA) in licorice that potently suppresses the growth of aggressive prostate cancer and sought to clarify its mechanism of action. We analyzed its inhibitory effects on the growth of PTEN-deleted human prostate cancer cells, in vitro and in vivo. Administration of IAA significantly attenuated the growth of prostate cancer cell cultures and xenograft tumors. These effects were found to be attributable to inhibition of the G1/S phase cell cycle transition and the accumulation of p27(kip1). The elevated p27(kip1) expression levels were concurrent with the decrease of its phosphorylation at threonine 187 through suppression of CDK2 kinase activity and the reduced phosphorylation of Akt at Serine 473 by diminishing the kinase activity of the mammalian target of rapamycin (mTOR). Further analysis using recombinant proteins and immunoprecipitated cell lysates determined that IAA exerts suppressive effects against CDK2 and mTOR kinase activity by direct binding with both proteins. These findings suggested that the licorice compound IAA is a potent molecular inhibitor of CDK2 and mTOR, with strong implications for the treatment of prostate cancer. Thus, licorice-derived extracts with high IAA content warrant further clinical investigation for nutritional sources for prostate cancer patients.
authors.affiliation: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.forename: Joe Eun
authors.initials: JE
authors.lastname: Son
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Lee
authors.forename: Yeong A
authors.initials: YA
authors.lastname: Kim
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Kim
authors.forename: Soon Sung
authors.initials: SS
authors.lastname: Lim
authors.forename: Jung Han Yoon
authors.initials: JH
authors.lastname: Park
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000187:drug effects*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007202:Indicators and Reagents; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007202:Indicators and Reagents; D007529:Isoflavones; C551631:isoangustone A; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019695:Glycyrrhizic Acid; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051357:Cyclin-Dependent Kinase 2
keywords: CDK2; Licorice; Prostate cancer; mTOR; p27(kip1)