Open AccessFormosanin C‐induced apoptosis requires activation of caspase‐2 and change of mitochondrial membrane potential
Author(s) -
Lee JenqChang,
Su ChunLi,
Chen LinLin,
Won ShenJeu
Publication year - 2009
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2008.01057.x
Subject(s) - apoptosis , cytochrome c , poly adp ribose polymerase , mitochondrion , dna fragmentation , microbiology and biotechnology , caspase , mitochondrial apoptosis induced channel , caspase 9 , caspase 3 , biology , mitochondrial permeability transition pore , phosphatidylserine , caspase 8 , chemistry , programmed cell death , biochemistry , polymerase , enzyme , membrane , phospholipid
Formosanin C is a pure compound isolated from Paris formosana Hayata (Liliaceae). The antitumor efficacy of formosanin C has been observed in cultured cells and animal systems. However, the molecular mechanisms of formosanin C remain unknown. The results of the present study indicate that formosanin C induced apoptosis of HT‐29 cells characterized by exposure of phosphatidylserine, accumulation of cells at the sub‐G 1 phase, fragmentation of DNA, and change of nuclear morphology in a time‐ and dose‐related manner. The apoptotic signaling cascades may proceed via proteolytic activation of caspase‐2, change of mitochondrial membrane potential (Δψ m ), release of cytochrome c and second mitochondria‐derived activator of caspase/direct IAP binding protein with low pI (Smac/DIABLO), activation of caspase‐9 and ‐3, and cleavage of poly(ADP‐ribose) polymerase (PARP). Increase in apoptosis‐inducing factor and endonuclease G expressions in nuclei, and increase in Bax and Bak expressions and decrease in Bcl‐X L expression on mitochondria were also observed in formosanin C‐treated HT‐29 cells. Attenuation of formosanin C‐induced change of Δψ m by caspase‐2 inhibitor (Z‐VDVAC) implies that caspase‐2 acts upstream of the mitochondria. Blockage of formosanin C‐induced apoptotic process by using either permeability transition pore inhibitor (cyclosporine A) or caspase‐9 inhibitor (Z‐LEHD) demonstrates the necessity of mitochondria and caspase‐9 in formosanin C‐induced apoptosis of HT‐29 cells. Taken together, the apoptotic mechanism of formosanin C in human colorectal cancer HT‐29 cells involves activation of caspase‐2 and the dysfunction of mitochondria. ( Cancer Sci 2009; 100: 503–513)