Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P42574 (
caspase-3
)
45,978
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Sigma-2 receptors have been implicated in both tumor proliferation and neurodegenerative diseases. Recently the sigma-2 receptor was identified as
transmembrane protein 97
(
TMEM97
). Progesterone receptor membrane component 1 (PGRMC1) was also recently reported to form a complex with
TMEM97
and the low density lipoprotein (LDL) receptor, and this trimeric complex is responsible for the rapid internalization of LDL. Sigma-2 receptor ligands with various structures have been shown to induce cell death in cancer cells. In the current study, we examined the role of
TMEM97
and PGRMC1 in mediating sigma-2 ligand-induced cell death. Cell viability and
caspase-3
assays were performed in control,
TMEM97
knockout (KO), PGRMC1 KO, and
TMEM97
/PGRMC1 double KO cell lines treated with several sigma-2 ligands. The data showed that knockout of
TMEM97
, PGRMC1, or both did not affect the concentrations of sigma-2 ligands that induced 50% of cell death (EC
50
), suggesting that cytotoxic effects of these compounds are not mediated by
TMEM97
or PGRMC1. Sigma-1 receptor ligands, (+)-pentazocine and NE-100, did not block sigma-2 ligand cytotoxicity, suggesting that sigma-1 receptor was not responsible for sigma-2 ligand cytotoxicity. We also examined whether the alternative, residual binding site (RBS) of 1,3-Di-
o
-tolylguanidine (DTG) could be responsible for sigma-2 ligand cytotoxicity. Our data showed that the binding affinities (
K
i
) of sigma-2 ligands on the DTG RBS did not correlate with the cytotoxicity potency (EC
50
) of these ligands, suggesting that the DTG RBS was not fully responsible for sigma-2 ligand cytotoxicity. In addition, we showed that knocking out
TMEM97
, PGRMC1, or both reduced the initial internalization rate of a sigma-2 fluorescent ligand,
SW120
. However, concentrations of internalized
SW120
became identical later in the control and knockout cells. These data suggest that the initial internalization process of sigma-2 ligands does not appear to mediate the cell-killing effect of sigma-2 ligands. In summary, we have provided evidence that sigma-2 receptor/
TMEM97
and PGRMC1 do not mediate sigma-2 ligand cytotoxicity. Our work will facilitate elucidating mechanisms of sigma-2 ligand cytotoxicity.
...
PMID:TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death. 3070 Oct 90
