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

被引:85
作者
Zeng, C. [1 ]
Rothfuss, J. [1 ]
Zhang, J. [1 ]
Chu, W. [1 ]
Vangveravong, S. [1 ]
Tu, Z. [1 ]
Pan, F. [1 ]
Chang, K. C. [2 ]
Hotchkiss, R. [2 ]
Mach, R. H. [1 ,3 ,4 ]
机构
[1] Washington Univ, Div Radiol Sci, Sch Med, Dept Radiol, St Louis, MO 63110 USA
[2] Washington Univ, Dept Anesthesiol, Sch Med, St Louis, MO 63110 USA
[3] Washington Univ, Dept Cell Biol & Physiol, Sch Med, St Louis, MO 63110 USA
[4] Washington Univ, Dept Biochem & Mol Biophys, Sch Med, St Louis, MO 63110 USA
关键词
sigma-2; receptors; apoptosis; autophagy; cell cycle; breast tumour cells; RECEPTOR LIGANDS; BINDING; PROLIFERATION; APOPTOSIS; AUTOPHAGY; CANCER; CYCLE; EXPRESSION; SIRAMESINE; BENZAMIDE;
D O I
10.1038/bjc.2011.602
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BACKGROUND: 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. METHODS: EMT-6 and MDA-MB-435 cells were treated with sigma-2 ligands. The modulation of multiple signaling pathways of cell death was evaluated. RESULTS: 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 mu M 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. CONCLUSION: Sigma-2 ligands induce cell death by multiple signalling pathways.
引用
收藏
页码:693 / 701
页数:9
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