Induction of apoptosis by Se-MSC in U937 human leukemia cells through release of cytochrome c and activation of caspases and PKC-delta: mutual regulation between caspases and PKC-delta via a positive feedback mechanism.

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-delta. 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-delta, suggesting activation of caspases is critical for the Se-MSC-induced apoptosis, and caspases lie upstream of PKC-delta. The Se-MSC-induced apoptosis of U937 cells also required activity of PKC-delta because pretreatment of rottlerin, a specific PKC-delta inhibitor greatly blocked the Se-MSC-induced apoptosis as well as processing and activities of caspases, suggesting activation of PKC-delta is also important for the Se-MSC-induced apoptosis of U937 cells, and PKC-delta 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-delta via a positive feedback mechanism, which may potentiate the apoptotic action by Se-MSC in U937 cells.

• Authors: Byeong-Churl Jang, Eun-Seok Choi, Ki-Jo Im, Won-Ki Baek, Taek Kyu Kwon, Min-Ho Suh, Sang-Pyo Kim, Jong-Wook Park, Seong-Il Suh
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 12 Issue 5 Pg. 733-9 (Nov 2003) ISSN: 1107-3756 [Print] Greece
• PMID: 14533002 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetophenones
• Benzopyrans
• Organoselenium Compounds
• Proto-Oncogene Proteins c-bcl-2
• Selenocysteine
• Cytochromes c
• rottlerin
• Poly(ADP-ribose) Polymerases
• PRKCD protein, human
• Protein Kinase C
• Protein Kinase C-delta
• Caspases
• Cysteine
• selenomethylselenocysteine

Topics

• Acetophenones (pharmacology)
• Apoptosis (drug effects)
• Benzopyrans (pharmacology)
• Caspases (metabolism)
• Cysteine (analogs & derivatives, pharmacology)
• Cytochromes c (metabolism)
• Enzyme Activation (drug effects)
• Feedback, Physiological
• Humans
• Organoselenium Compounds (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein Kinase C (metabolism)
• Protein Kinase C-delta
• Protein Transport (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Selenocysteine (analogs & derivatives)
• U937 Cells