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: Eunjung Lee, Joe Eun Son, Sanguine Byun, Seung Joon Lee, Yeong A Kim, Kangdong Liu, Jiyoung Kim, Soon Sung Lim, Jung Han Yoon Park, Zigang Dong, Ki Won Lee, Hyong Joo Lee
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 272 Issue 1 Pg. 12-20 (Oct 01 2013) ISSN: 1096-0333 [Electronic] United States
• PMID: 23707764 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Indicators and Reagents
• Isoflavones
• isoangustone A
• Cyclin-Dependent Kinase Inhibitor p27
• Glycyrrhizic Acid
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Cyclin-Dependent Kinase 2

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase 2 (drug effects)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Enzyme Activation (drug effects)
• Fluorescent Antibody Technique
• Glycyrrhizic Acid (pharmacology)
• Humans
• Immunohistochemistry
• Immunoprecipitation
• Indicators and Reagents
• Isoflavones (pharmacology)
• Male
• Mice
• Mice, Inbred BALB C
• Phosphorylation
• Prostatic Neoplasms (drug therapy)
• TOR Serine-Threonine Kinases (drug effects)
• Xenograft Model Antitumor Assays