title: Sigma-2 ligands induce tumour cell death by multiple signalling pathways.
abstract: 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 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.
  
  
  CONCLUSIONS
  Sigma-2 ligands induce cell death by multiple signalling pathways.
authors.affiliation: Department of Radiology, Division of Radiological Sciences, Washington University School of Medicine, 510 S Kingshighway Boulevard, St Louis, MO 63110, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zeng
authors.forename: J
authors.initials: J
authors.lastname: Rothfuss
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: W
authors.initials: W
authors.lastname: Chu
authors.forename: S
authors.initials: S
authors.lastname: Vangveravong
authors.forename: Z
authors.initials: Z
authors.lastname: Tu
authors.forename: F
authors.initials: F
authors.lastname: Pan
authors.forename: K C
authors.initials: KC
authors.lastname: Chang
authors.forename: R
authors.initials: R
authors.lastname: Hotchkiss
authors.forename: R H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D008024:Ligands; D051379:Mice; D017480:Receptors, sigma / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D017480:Receptors, sigma; C106107:sigma-2 receptor