Article

Sigma-2 ligands induce tumour cell death by multiple signalling pathways.

Department of Radiology, Division of Radiological Sciences, Washington University School of Medicine, 510 S Kingshighway Boulevard, St Louis, MO 63110, USA.
British Journal of Cancer (impact factor: 5.04). 02/2012; 106(4):693-701. DOI:10.1038/bjc.2011.602 pp.693-701
Source: PubMed

ABSTRACT The sigma-2 receptor has been identified as a biomarker of proliferating cells in solid tumours. In the present study, we studied the mechanisms of sigma-2 ligand-induced cell death in the mouse breast cancer cell line EMT-6 and the human melanoma cell line MDA-MB-435.
EMT-6 and MDA-MB-435 cells were treated with sigma-2 ligands. The modulation of multiple signaling pathways of cell death was evaluated.
Three sigma-2 ligands (WC-26, SV119 and RHM-138) induced DNA fragmentation, caspase-3 activation and PARP-1 cleavage. The caspase inhibitor Z-VAD-FMK partially blocked DNA fragmentation and cytotoxicity caused by these compounds. These data suggest that sigma-2 ligand-induced apoptosis and caspase activation are partially responsible for the cell death. WC-26 and siramesine induced formation of vacuoles in the cells. WC-26, SV119, RHM-138 and siramesine increased the synthesis and processing of microtubule-associated protein light chain 3, an autophagosome marker, and decreased the expression levels of the downstream effectors of mammalian target of rapamycin (mTOR), p70S6K and 4EBP1, suggesting that sigma-2 ligands induce autophagy, probably by inhibition of the mTOR pathway. All four sigma-2 ligands decreased the expression of cyclin D1 in a time-dependent manner. In addition, WC-26 and SV119 mainly decreased cyclin B1, E2 and phosphorylation of retinoblastoma protein (pRb); RHM-138 mainly decreased cyclin E2; and 10 μM siramesine mainly decreased cyclin B1 and pRb. These data suggest that sigma-2 ligands also impair cell-cycle progression in multiple phases of the cell cycle.
Sigma-2 ligands induce cell death by multiple signalling pathways.

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Keywords

10 μM siramesine
 
caspase activation
 
caspase inhibitor Z-VAD-FMK
 
caspase-3 activation
 
cyclin B1
 
cyclin D1
 
cyclin E2
 
expression levels
 
human melanoma cell line MDA-MB-435
 
microtubule-associated protein light chain 3
 
mTOR pathway
 
multiple phases
 
multiple signaling pathways
 
multiple signalling pathways
 
PARP-1 cleavage
 
sigma-2 ligand-induced apoptosis
 
sigma-2 ligand-induced cell death
 
sigma-2 ligands induce autophagy
 
siramesine induced formation
 
time-dependent manner