4-O-methylhonokiol, a PPARγ Agonist, Inhibits Prostate Tumour Growth: P21-mediated Suppression of NF-κB Activity

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2012 Oct 10

PMID 23043610

Citations 14

Authors

N J Lee

J H Oh

J O Ban

J H Shim

H P Lee

J K Jung

B W Ahn

D Y Yoon

S B Han

Y W Ham

J T Hong

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: The effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, were investigated on human prostate cancer cells and its mechanism of action elucidated.

Experimental Approach: The anti-cancer effects of MH were examined in prostate cancer and normal cells. The effects were validated in vivo using a mouse xenograft model.

Key Results: MH increased the expression of PPARγ in prostate PC-3 and LNCap cells. The pull-down assay and molecular docking study indicated that MH directly binds to PPARγ. MH also increased transcriptional activity of PPARγ but decreased NF-κB activity. MH inhibited the growth of human prostate cancer cells, an effect attenuated by the PPARγ antagonist GW9662. MH induced apoptotic cell death and this was related to G(0) -G(1) phase cell cycle arrest. MH increased the expression of the cell cycle regulator p21, and apoptotic proteins, whereas it decreased phosphorylation of Rb and anti-apoptotic proteins. Transfection of PC3 cells with p21 siRNA or a p21 mutant plasmid on the cyclin D1/ cycline-dependent kinase 4 binding site abolished the effects of MH on cell growth, cell viability and related protein expression. In the animal studies, MH inhibited tumour growth, NF-κB activity and expression of anti-apoptotic proteins, whereas it increased the transcriptional activity and expression of PPARγ, and the expression of apoptotic proteins and p21 in tumour tissues.

Conclusions And Implication: MH inhibits growth of human prostate cancer cells through activation of PPARγ, suppression of NF-κB and arrest of the cell cycle. Thus, MH might be a useful tool for treatment of prostate cancer.

Citing Articles

Anti-Inflammatory and Anticancer Effects of Kaurenoic Acid in Overcoming Radioresistance in Breast Cancer Radiotherapy.

Kim T, Ko S Nutrients. 2025; 16(24.

PMID: 39770941 PMC: 11677055. DOI: 10.3390/nu16244320.

Polygalacic acid attenuates cognitive impairment by regulating inflammation through PPARγ/NF-κB signaling pathway.

Zhao T, Jia J CNS Neurosci Ther. 2024; 30(2):e14581.

PMID: 38421141 PMC: 10851321. DOI: 10.1111/cns.14581.

ESS2 controls prostate cancer progression through recruitment of chromodomain helicase DNA binding protein 1.

Takahashi S, Takada I, Hashimoto K, Yokoyama A, Nakagawa T, Makishima M Sci Rep. 2023; 13(1):12355.

PMID: 37524814 PMC: 10390525. DOI: 10.1038/s41598-023-39626-0.

Comparative Study of Docosahexaenoic Acid with Different Molecular Forms for Promoting Apoptosis of the 95D Non-Small-Cell Lung Cancer Cells in a PPARγ-Dependent Manner.

Yue H, Tian Y, Zhao Z, Bo Y, Guo Y, Wang J Mar Drugs. 2022; 20(10).

PMID: 36286423 PMC: 9604550. DOI: 10.3390/md20100599.

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer.

Xu R, Luo X, Ye X, Li H, Liu H, Du Q Front Oncol. 2021; 11:682762.

PMID: 34381712 PMC: 8351465. DOI: 10.3389/fonc.2021.682762.

References

Lee S, Yuk D, Song H, Yoon D, Jung J, Moon D . Growth inhibitory effects of obovatol through induction of apoptotic cell death in prostate and colon cancer by blocking of NF-kappaB. Eur J Pharmacol. 2008; 582(1-3):17-25. DOI: 10.1016/j.ejphar.2007.12.027. View

Sue Y, Chung C, Lin H, Chou Y, Jen C, Li H . PPARdelta-mediated p21/p27 induction via increased CREB-binding protein nuclear translocation in beraprost-induced antiproliferation of murine aortic smooth muscle cells. Am J Physiol Cell Physiol. 2009; 297(2):C321-9. DOI: 10.1152/ajpcell.00069.2009. View

Chang P, Miyamoto S . Nuclear factor-kappaB dimer exchange promotes a p21(waf1/cip1) superinduction response in human T leukemic cells. Mol Cancer Res. 2006; 4(2):101-12. DOI: 10.1158/1541-7786.MCR-05-0259. View

Lee Y, Lee Y, Lee C, Jung J, Han S, Hong J . Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther. 2011; 130(2):157-76. DOI: 10.1016/j.pharmthera.2011.01.010. View

Oh J, Kang L, Ban J, Kim Y, Kim K, Han S . Anti-inflammatory effect of 4-O-methylhonokiol, compound isolated from Magnolia officinalis through inhibition of NF-kappaB [corrected]. Chem Biol Interact. 2009; 180(3):506-14. DOI: 10.1016/j.cbi.2009.03.014. View

Ghosh A, Steele R, Ray R . Knockdown of MBP-1 in human prostate cancer cells delays cell cycle progression. J Biol Chem. 2006; 281(33):23652-7. DOI: 10.1074/jbc.M602930200. View

Palozza P, Colangelo M, Simone R, Catalano A, Boninsegna A, Lanza P . Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines. Carcinogenesis. 2010; 31(10):1813-21. DOI: 10.1093/carcin/bgq157. View

Park K, Choi K, Kim H, Kim K, Lee M, Lee J . Isoflavone-deprived soy peptide suppresses mammary tumorigenesis by inducing apoptosis. Exp Mol Med. 2009; 41(6):371-81. PMC: 2705857. DOI: 10.3858/emm.2009.41.6.042. View

Lee S, Kim H, Cho Y, Park K, Kim E, Jung K . Aqueous extract of Magnolia officinalis mediates proliferative capacity, p21WAF1 expression and TNF-alpha-induced NF-kappaB activity in human urinary bladder cancer 5637 cells; involvement of p38 MAP kinase. Oncol Rep. 2007; 18(3):729-36. View

10.

Wolf I, OKelly J, Wakimoto N, Nguyen A, Amblard F, Karlan B . Honokiol, a natural biphenyl, inhibits in vitro and in vivo growth of breast cancer through induction of apoptosis and cell cycle arrest. Int J Oncol. 2007; 30(6):1529-37. View

11.

Oh J, Ban J, Cho M, Jo M, Jung J, Ahn B . 4-O-methylhonokiol inhibits colon tumor growth via p21-mediated suppression of NF-κB activity. J Nutr Biochem. 2011; 23(7):706-15. DOI: 10.1016/j.jnutbio.2011.03.013. View

12.

Fried L, Arbiser J . Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxid Redox Signal. 2009; 11(5):1139-48. PMC: 2842137. DOI: 10.1089/ars.2009.2440. View

13.

Hahm E, Arlotti J, Marynowski S, Singh S . Honokiol, a constituent of oriental medicinal herb magnolia officinalis, inhibits growth of PC-3 xenografts in vivo in association with apoptosis induction. Clin Cancer Res. 2008; 14(4):1248-57. DOI: 10.1158/1078-0432.CCR-07-1926. View

14.

Suh J, Rabson A . NF-kappaB activation in human prostate cancer: important mediator or epiphenomenon?. J Cell Biochem. 2003; 91(1):100-17. DOI: 10.1002/jcb.10729. View

15.

Yu C, Kan S, Pu H, Chien E, Wang P . Apoptotic signaling in bufalin- and cinobufagin-treated androgen-dependent and -independent human prostate cancer cells. Cancer Sci. 2008; 99(12):2467-76. PMC: 11159935. DOI: 10.1111/j.1349-7006.2008.00966.x. View

16.

Biggs J, Kraft A . Inhibitors of cyclin-dependent kinase and cancer. J Mol Med (Berl). 1995; 73(10):509-14. DOI: 10.1007/BF00198902. View

17.

Jarvis M, Gray T, Palmer C . Both PPARgamma and PPARdelta influence sulindac sulfide-mediated p21WAF1/CIP1 upregulation in a human prostate epithelial cell line. Oncogene. 2005; 24(55):8211-5. DOI: 10.1038/sj.onc.1208983. View

18.

Waku T, Shiraki T, Oyama T, Morikawa K . Atomic structure of mutant PPARgamma LBD complexed with 15d-PGJ2: novel modulation mechanism of PPARgamma/RXRalpha function by covalently bound ligands. FEBS Lett. 2008; 583(2):320-4. DOI: 10.1016/j.febslet.2008.12.017. View

19.

Shim J, Choi H, Pugliese A, Lee S, Chae J, Choi B . (-)-Epigallocatechin gallate regulates CD3-mediated T cell receptor signaling in leukemia through the inhibition of ZAP-70 kinase. J Biol Chem. 2008; 283(42):28370-9. PMC: 2568917. DOI: 10.1074/jbc.M802200200. View

20.

Chen F, Wang T, Wu Y, Gu Y, Xu X, Zheng S . Honokiol: a potent chemotherapy candidate for human colorectal carcinoma. World J Gastroenterol. 2004; 10(23):3459-63. PMC: 4576227. DOI: 10.3748/wjg.v10.i23.3459. View