Induction of apoptosis by Se-MSC in U937 human leukemia cells through release of cytochrome c and activation of caspases and PKC-δ: mutual regulation between caspases and PKC-δ via a positive feedback mechanism
- Affiliated Author(s)
- 장병철; 김상표; 권택규; 박종욱; 백원기; 서민호; 서성일
- Alternative Author(s)
- Jang, Byeong Churl; Kim, Sang Pyo; Kwon, Taeg Kyu; Park, Jong Wook; Baek, Won Ki; Suh, Min Ho; Suh, Seong Il
- Journal Title
- International Journal of Molecular Medicine
- ISSN
- 1107-3756
- Issued Date
- 2003
- Abstract
- Se-methylselenocysteine (Se-MSC) has been shown to possess potent chemopreventive and anti-tumor properties. However, its exact mechanism of action is still not well understood. The present study investigated the mechanism of Se-MSC on the induction of apoptosis using U937 human leukemia cells. Se-MSC induced dose- and time-dependent apoptosis of U937 cells as assessed by flow cytometry analysis, DNA fragmentation, and proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP). Se-MSC increased time- and dose-dependent cytochrome c accumulation in the cytosol, which was greatly inhibited by overexpression of Bcl-2, suggesting that the apoptotic effect by Se-MSC in U937 cells is mitochondrial-dependent. Se-MSC also induced activation of caspases, followed by proteolytic cleavage of PKC-δ. The Se-MSC-induced apoptosis required activities of caspases since pretreatment of a pan-caspase inhibitor z-VAD-fmk greatly suppressed the Se-MSC-induced apoptosis as well as proteolytic cleavage of PKC-δ, suggesting activation of caspases is critical for the Se-MSC-induced apoptosis, and caspases lie upstream of PKC-δ. The Se-MSC-induced apoptosis of U937 cells also required activity of PKC-δ because pretreatment of rottlerin, a specific PKC-δ inhibitor greatly blocked the Se-MSC-induced apoptosis as well as processing and activities of caspases, suggesting activation of PKC-δ is also important for the Se-MSC-induced apoptosis of U937 cells, and PKC-δ lies upstream of caspases. Together, our data suggest the apoptotic mechanism by Se-MSC in U937 cells may be related to cytochrome c release from the mitochondria, and mutual activation between caspases and PKC-δ via a positive feedback mechanism, which may potentiate the apoptotic action by Se-MSC in U937 cells.
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