Sigma-2 ligands induce tumour cell death by multiple signalling pathways.
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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ABSTRACT: sigma 1 and sigma 2 receptors have been shown to exist in a number of rodent and human tumor cell lines. Although their expression is heterogeneous and their function is unknown, sigma receptors have been proposed as potential targets for diagnostic tumor-imaging agents. In this study, the density of sigma 2 receptors in proliferative (P) and quiescent (Q) cells of the mouse mammary adenocarcinoma, line 66, was examined. Scatchard analyses of sigma 2 receptors were performed on membrane preparations of 66 P cells from 3-day cultures and 66 Q cells from 7-, 10-, and 12-day cultures. The Scatchard studies revealed that 66 P cells had approximately 10 times more sigma 2 receptors/cell than the 66 Q cells from 10-day cultures. Although > 97% of the cells were quiescent after 7 days in culture, the maximum differential in the sigma 2 expression between 66 P and 66 Q cells was not attained until these cells had been in culture for 10 days. These data suggest that ligands labeled with positron-emitting or single photon-emitting radionuclides, which selectively bind sigma 2 receptors, have the potential to noninvasively assess the proliferative status of human breast tumors.Cancer Research 01/1997; 57(1):156-61. · 7.86 Impact Factor
European Journal of Nuclear Medicine 03/2001; 28(2):133-5.