2015 ; Vol.25-3: 334~342
|Author||Seungyeon Hyun, Man Sub Kim, Yong Seok Song, Yesol Bak, Sun Young Ham, Dong Hun Lee, Jintae Hong, Do Young Yoon|
|Place of duty||Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea|
|Title||Peroxisome Proliferator-Activated Receptor-Gamma Agonist 4-O-Methylhonokiol Induces Apoptosis by Triggering the Intrinsic Apoptosis Pathway and Inhibiting the PI3K/Akt Survival Pathway in SiHa Human Cervical Cancer Cells|
J. Microbiol. Biotechnol.2015 ;
|Abstract||4-O-Methylhonokiol (MH), a bioactive compound derived from Magnolia officinalis, is known
to exhibit antitumor effects in various cancer cells. However, the precise mechanism of its
anticancer activity in cervical cancer cells has not yet been studied. In this study, we
demonstrated that MH induces apoptosis in SiHa cervical cancer cells by enhancing
peroxisome proliferator-activated receptor-gamma (PPARγ) activation, followed by inhibition
of the PI3K/Akt pathway and intrinsic pathway induction. MH upregulated PPARγ and PTEN
expression levels while it decreased p-Akt in the MH-induced apoptotic process, thereby
supporting the fact that MH is a PPARγ activator. Additionally, MH decreased the expression
of Bcl-2 and Bcl-XL, inducing the intrinsic pathway in MH-treated SiHa cells. Furthermore,
MH treatment led to the activation of caspase-3/caspase-9 and proteolytic cleavage of
polyADP ribose polymerase. The expression levels of Fas (CD95) and E6/E7 oncogenes were
not altered by MH treatment. Taken together, MH activates PPARγ/PTEN expression and
induces apoptosis via suppression of the PI3K/Akt pathway and mitochondria-dependent
pathways in SiHa cells. These findings suggest that MH has potential for development as a
therapeutic agent for human cervical cancer.|
|Key_word||4-O-methylhonokiol, cervical cancer, PPARγ agonist, apoptosis|
Amblard F, Delinsky D, Arbiser JL, Schinazi RF. 2006. Facile purification of honokiol and its antiviral and cytotoxic properties. J. Med. Chem. 49: 3426-3427.
Arora S, Singh S, Piazza GA, Contreras CM, Panyam J, Singh AP. 2012. Honokiol: a novel natural agent for cancer prevention and therapy. Curr. Mol. Med. 12: 1244-1252.
Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. 2002. The causal relation between human papillomavirus and cervical cancer. J. Clin. Pathol. 55: 244-265.
Cantley LC. 2002. The phosphoinositide 3-kinase pathway. Science 296: 1655-1657.
Chen L, Liu Q, Qin R, Le H, Xia R, Li W, Kumar M. 2005. Amplification and functional characterization of MUC1 promoter and gene-virotherapy via a targeting adenoviral vector expressing hSSTR2 gene in MUC1-positive Panc-1 pancreatic cancer cells in vitro. Int. J. Mol. Med. 15: 617-626.
Chipuk JE, Green DR. 2008. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol. 18: 157-164.
Datta SR, Brunet A, Greenberg ME. 1999. Cellular survival:a play in three Akts. Genes Dev. 13: 2905-2927.
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. 1997. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91: 231-241.
Duronio V, Scheid MP, Ettinger S. 1998. Downstream signalling events regulated by phosphatidylinositol 3-kinase activity. Cell Signal. 10: 233-239.
Eibl G, Wente MN, Reber HA, Hines OJ. 2001. Peroxisome proliferator-activated receptor gamma induces pancreatic cancer cell apoptosis. Biochem. Biophys. Res. Commun. 287:522-529.
Elrod HA, Sun SY. 2008. PPARgamma and apoptosis in cancer. PPAR Res. 2008: 704165.
Fujita M, Tohji C, Honda Y, Yamamoto Y, Nakamura T, Yagami T, et al. 2012. Cytotoxicity of 15-deoxy-delta(12,14)prostaglandin J(2) through PPARgamma-independent pathway and the involvement of the JNK and Akt pathway in renal cell carcinoma. Int. J. Med. Sci. 9: 555-566.
Harima Y, Sawada S, Nagata K, Sougawa M, Ostapenko V, Ohnishi T. 2001. Mutation of the PTEN gene in advanced cervical cancer correlated with tumor progression and poor outcome after radiotherapy. Int. J. Oncol. 18: 493-497.
Hu H, Zhang XX, Wang YY, Chen SZ. 2005. Honokiol inhibits arterial thrombosis through endothelial cell protection and stimulation of prostacyclin. Acta Pharmacol. Sin. 26:1063-1068.
Jiang BH, Liu LZ. 2008. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim. Biophys. Acta 1784: 150-158.
Jiang BH, Zheng JZ, Aoki M, Vogt PK. 2000. Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc. Natl. Acad. Sci. USA 97: 1749-1753.
Kang JS, Lee KH, Han MH, Lee H, Ahn JM, Han SB, et al. 2008. Antiinflammatory activity of methanol extract isolated from stem bark of Magnolia kobus. Phytother. Res. 22: 883-888.
Klaes R, Woerner SM, Ridder R, Wentzensen N, Duerst M, Schneider A, et al. 1999. Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res. 59: 6132-6136.
Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM. 1992. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358: 771-774.
Lee NJ, Oh JH, Ban JO, Shim JH, Lee HP, Jung JK, et al. 2013. 4-O-Methylhonokiol, a PPARgamma agonist, inhibits prostate tumour growth: p21-mediated suppression of NFkappaB activity. Br. J. Pharmacol. 168: 1133-1145.
Lee YJ, Lee YM, Lee CK, Jung JK, Han SB, Hong JT. 2011. Therapeutic applications of compounds in the Magnolia family. Pharmacol. Ther. 130: 157-176.
Lehrke M, Lazar MA. 2005. The many faces of PPARgamma. Cell 123: 993-999.
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X. 1997. Cytochrome c and dATPdependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91: 479-489.
Lowe SW, Cepero E, Evan G. 2004. Intrinsic tumour suppression. Nature 432: 307-315.
Martin MC, Allan LA, Lickrish M, Sampson C, Morrice N, Clarke PR. 2005. Protein kinase A regulates caspase-9 activation by Apaf-1 downstream of cytochrome c. J. Biol. Chem. 280:15449-15455.
Oh JH, Ban JO, Cho MC, Jo M, Jung JK, Ahn B, et al. 2012. 4-O-Methylhonokiol inhibits colon tumor growth via p21mediated suppression of NF-kappaB activity. J. Nutr. Biochem. 23: 706-715.
Park J, Lee J, Jung E, Park Y, Kim K, Park B, et al. 2004. In vitro antibacterial and anti-inflammatory effects of honokiol and magnolol against Propionibacterium sp. Eur. J. Pharmacol. 496: 189-195.
Rocchi S, Auwerx J. 1999. Peroxisome proliferator-activated receptor-gamma: a versatile metabolic regulator. Ann. Med. 31: 342-351.
Schwarz JK, Payton JE, Rashmi R, Xiang T, Jia Y, Huettner P, et al. 2012. Pathway-specific analysis of gene expression data identifies the PI3K/Akt pathway as a novel therapeutic target in cervical cancer. Clin. Cancer Res. 18: 1464-1471.
Sertznig P, Seifert M, Tilgen W, Reichrath J. 2007. Present concepts and future outlook: function of peroxisome proliferatoractivated receptors (PPARs) for pathogenesis, progression, and therapy of cancer. J. Cell. Physiol. 212: 1-12.
Shimada T, Kojima K, Yoshiura K, Hiraishi H, Terano A. 2002. Characteristics of the peroxisome proliferator activated receptor gamma (PPARgamma) ligand induced apoptosis in colon cancer cells. Gut 50: 658-664.
Susin SA, Daugas E, Ravagnan L, Samejima K, Zamzami N, Loeffler M, et al. 2000. Two distinct pathways leading to nuclear apoptosis. J. Exp. Med. 192: 571-580.
Tait SW, Green DR. 2010. Mitochondria and cell death:outer membrane permeabilization and beyond. Nat. Rev. Mol. Cell Biol. 11: 621-632.
Tan ML, Ooi JP, Ismail N, Moad AI, Muhammad TS. 2009. Programmed cell death pathways and current antitumor targets. Pharm. Res. 26: 1547-1560.
Tsubouchi Y, Sano H, Kawahito Y, Mukai S, Yamada R, Kohno M, et al. 2000. Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptorgamma agonists through induction of apoptosis. Biochem. Biophys. Res. Commun. 270: 400-405.
Voutsadakis IA. 2007. Peroxisome proliferator-activated receptor gamma (PPARgamma) and colorectal carcinogenesis. J. Cancer Res. Clin. Oncol. 133: 917-928.
Weeks BS. 2009. Formulations of dietary supplements and herbal extracts for relaxation and anxiolytic action: Relarian. Med. Sci. Monit. 15: RA256-RA262.
Woo CC, Loo SY, Gee V, Yap CW, Sethi G, Kumar AP, Tan KH. 2011. Anticancer activity of thymoquinone in breast cancer cells: possible involvement of PPAR-gamma pathway. Biochem. Pharmacol. 82: 464-475.
Zimmermann KC, Bonzon C, Green DR. 2001. The machinery of programmed cell death. Pharmacol. Ther. 92: 57-70.