The mechanism of ellipticine-induced apoptosis and cell cycle arrest in human breast MCF-7 cancer cells.
Ellipticine, a cytotoxic plant alkaloid, is known to inhibit topoisomerase II. Here, we first report the molecular mechanism of ellipticine's apoptotic action in human breast MCF-7 cancer cells. Treatment of cells with ellipticine resulted in inhibition of growth, and G2/M phase arrest of the cell cycle. This effect was associated with a marked increase in the protein expression of p53 and, p21/WAF1 and KIP1/p27, but not of WAF1/p21. Ellipticine treatment increased the expression of Fas/APO-1 and its ligands, mFas ligand and sFas ligand, and subsequent activation of caspase-8. The mitochondrial apoptotic pathway amplified the Fas/Fas ligand death receptor pathway by Bid interaction. This effect was found to result in a significant increase in activation of caspase-9. Taken together, we have concluded that the molecular mechanisms during ellipticine-mediated growth inhibition and induction of apoptosis in MCF-7 cells were due to (1) cell cycle arrest and induction of apoptosis, (2) induction of p53 and KIP1/p27 expression, (3) triggering of Fas/Fas ligand pathway, (4) disruption of mitochondrial function, and (5) the apoptotic signaling was amplified by cross-talk between Fas death receptor and mitochondrial apoptotic pathway.
Kuo
Po-Lin
PL
Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan, ROC.
Hsu
Ya-Ling
YL
Chang
Cheng-Hsiung
CH
Lin
Chun-Ching
CC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis*; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004611:Ellipticines / Q000494:pharmacology*; D053222:Fas Ligand Protein; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008928:Mitochondria; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D000970:Antineoplastic Agents; C436291:CDKN1B protein, human; D002352:Carrier Proteins; D004611:Ellipticines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016159:Tumor Suppressor Protein p53; C034192:ellipticine; D050760:Cyclin-Dependent Kinase Inhibitor p27