Honokiol causes G0-G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity.

Abstract

The present study was undertaken to gain insights into the mechanism of cell cycle arrest caused by honokiol, a constituent of oriental herb Magnolia officinalis. The honokiol treatment decreased the viability of PC-3 and LNCaP human prostate cancer cells in a concentration- and time-dependent manner, which correlated with G0-G1 phase cell cycle arrest. The honokiol-mediated cell cycle arrest was associated with a decrease in protein levels of cyclin D1, cyclin-dependent kinase 4 (Cdk4), Cdk6, and/or cyclin E and suppression of complex formation between cyclin D1 and Cdk4 as revealed by immunoprecipitation using anti-cyclin D1 antibody followed by immunoblotting for Cdk4 protein. The honokiol-treated PC-3 and LNCaP cells exhibited a marked decrease in the levels of total and phosphorylated retinoblastoma protein (Rb), which correlated with the suppression of transcriptional activity of E2F1. Exposure of PC-3 and LNCaP cells to honokiol resulted in the induction of p21 (PC-3 and LNCaP) and p53 protein expression (LNCaP). However, small interfering RNA (siRNA)-mediated knockdown of either p21 (PC-3 and LNCaP) or p53 (LNCaP) protein failed to confer any protection against honokiol-induced cell cycle arrest. The honokiol treatment caused the generation of reactive oxygen species (ROS), and the cell cycle arrest caused by honokiol was partially but significantly attenuated in the presence of antioxidant N-acetylcysteine. In conclusion, the present study reveals that the honokiol-mediated G0-G1 phase cell cycle arrest in human prostate cancer cells is associated with the suppression of protein level/phosphorylation of Rb leading to inhibition of transcriptional activity of E2F1.

• Authors: Eun-Ryeong Hahm, Shivendra V Singh
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 10 Pg. 2686-95 (Oct 2007) ISSN: 1535-7163 [Print] United States
• PMID: 17938262 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents, Phytogenic
• Antioxidants
• Biphenyl Compounds
• CDKN1A protein, human
• Cell Cycle Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Drugs, Chinese Herbal
• E2F1 Transcription Factor
• E2F1 protein, human
• Lignans
• RNA, Small Interfering
• Reactive Oxygen Species
• Retinoblastoma Protein
• Tumor Suppressor Protein p53
• honokiol
• Luciferases
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Antioxidants (pharmacology)
• Biphenyl Compounds (pharmacology)
• Cell Cycle (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (antagonists & inhibitors, genetics, metabolism)
• Drugs, Chinese Herbal
• E2F1 Transcription Factor (genetics, metabolism)
• G1 Phase (drug effects)
• Humans
• Immunoprecipitation
• Lignans (pharmacology)
• Luciferases (metabolism)
• Male
• Phosphorylation
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• RNA, Small Interfering (pharmacology)
• Reactive Oxygen Species (metabolism)
• Resting Phase, Cell Cycle (drug effects)
• Retinoblastoma Protein (metabolism)
• Transcription, Genetic (drug effects)
• Tumor Cells, Cultured (drug effects)
• Tumor Suppressor Protein p53 (metabolism)