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 p27kip1. The elevated p27kip1 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.
Bibliographical noteFunding Information:
This study was supported by a grant from the BioGreen21 Program (Nos. 20100301-061-068-001-06-00 ), the Rural Development Administration , the Mid-career Researcher Program ( 2010-0006923 ), the Global Frontier Project grant ( NRF-M1AXA002-2012M3A6A4054949 ), the World Class University Program ( R31-2008-00-10056-0 ), Leap Research Program of the National Research Foundation of Korea ( 2010-0029233 ) funded by the Ministry of Education, Science and Technology of Korea, Republic of Korea. All authors have declared that no conflict of interest exists.
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