Taiwanin A inhibits MCF-7 cancer cell activity through induction of oxidative stress, upregulation of DNA damage checkpoint kinases, and activation of p53 and FasL/Fas signaling pathways.
This study investigates the anti-MCF-7 breast cancer cell effects and the underlying pharmacological activity and mechanism of taiwanin A, a major lignan isolated from Taiwania cryptomerioides. Our results show that taiwanin A time-dependently induced reactive oxygen species level and DNA damage in MCF-7 cells, which were likely activated kinases ataxia telangiectasia mutated (ATM) and checkpoint kinase (Chk). Taiwanin A could also up-regulate p53, phosphorylated p53, p21(Cip1), and p27(Kip1) and down-regulate the G(2)/M checkpoint cyclin-dependent kinase1 (Cdk1)-cyclin A/B, leading to induction of G(2)/M cell-cycle arrest in MCF-7 cells. Blockade of p53 gene expression by siRNA further demonstrated that the cell-cycle arrest induced by taiwanin A was p53-dependent. The FasL/Fas-mediated apoptotic signaling cascade was involved in taiwanin A-induced apoptosis via activation of caspases-10 and -7 (but not caspase-8), and proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). In contrast, mitochondria-initiated apoptotic pathway was not involved. This is the first report to delineate novel mechanism of the action of taiwanin A against MCF-7 cells, suggesting this lignan may have value for development as an anti-breast cancer agent.
Shyur
Lie-Fen
LF
Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC. lfshyur@ccvax.sinica.edu.tw
Lee
Shu-Hua
SH
Chang
Shang-Tzen
ST
Lo
Chiu-Ping
CP
Kuo
Yueh-Hsiung
YH
Wang
Sheng-Yang
SY
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D029779:Cupressaceae / Q000737:chemistry*; D004249:DNA Damage / Q000502:physiology*; D005260:Female; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017705:Lignans / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D018547:Plant Stems; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011116:Polynucleotide 5'-Hydroxyl-Kinase / Q000378:metabolism; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C491901:FAS protein, human; D005663:Furans; D017705:Lignans; D010936:Plant Extracts; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C419332:taiwanin A; D011065:Poly(ADP-ribose) Polymerases; D011116:Polynucleotide 5'-Hydroxyl-Kinase; D020169:Caspases