Antiproliferative effects of SR31747A in animal cell lines are mediated by inhibition of cholesterol biosynthesis at the sterol isomerase step

Abstract

SR31747A is a new sigma ligand exhibiting immunosuppressive properties and antiproliferative activity on lymphocyte cells. Only two subtypes of sigma receptor, namely the sigma 1 receptor and emopamilbinding protein, have been characterised molecularly. Only the σ 1 receptor has been shown to bind (Z)Ncyclohexyl-N-ethyl-3-(3-chloro4-cyclohexylphenyl)propen-2-ylamine hydrochloride (SR31747A) with high affinity. It was demonstrated that the SR31747A effect on the inhibition of T-cell proliferation was consistent with a sigma 1 receptor-mediated event. In this report, binding experiments and sterol isomerase assays, using recombinant yeast strains, indicate that the recently cloned emopamil-binding protein is a new SR31747A-binding protein whose activity is inhibited by SR31747A. Sterol analyses reveal the accumulation of a ∆8-cholesterol isomer at the expense of cholesterol in SR31747A-treated cells, suggesting that cholesterol biosynthesis is inhibited by SR31747A at the ∆8-∆7 sterol isomerase step in animal cells. This observation is consistent with a sterol isomerase role of the emopamil-binding protein in the cholesterol biosynthetic pathway in animal cells. In contrast, there is no evidence for such a role of the sigma 1 receptor, in spite of the structural similarity shared by this protein and yeast sterol isomerase. We have found that SR31747A also exerts anti-proliferative effects at nanomolar concentrations on various established cell lines. The antiproliferative activity of SR31747A is reversed by cholesterol. Sterol-isomerase overproduction enhances resistance of CHO cells. This last observation strongly suggests that sterol isomerase is implicated in the antiproliferative effect of the drug in established cell lines.

Histopathological alterations in organ structures of hypercholesterolemic rats fed Ortanique peel polymethoxylated flavones

“…This positive effect on proliferation may be explained by the fact that the cholesterol biosynthetic pathway provides several compounds that are essential for cell growth and division, such as mevalonic acid, farnesyl pyrophosphate, and cholesterol 35–37 . Studies also show that inhibitors of cholesterol biosynthesis inhibit cell proliferation 38 . We have previously reported that PMF ort reduces the activity of HMG‐CoA reductase, a key enzyme in cholesterol biosynthesis 17 .…”

Sterol metabolism and ERG2 gene regulation in the yeast Saccharomyces cerevisiae

“…SR31747A is a highly selective Δ8‐Δ7‐sterol isomerase inhibitor that is effective against the yeast enzyme [5] as well as against the structurally and phylogenetically unrelated mammalian Δ8‐Δ7‐sterol isomerase [2,6,7]. SR31747A displays immunosuppressive properties [8] that appear to be mediated by the ERG2 ortholog in mammals, namely the subtype 1 of the so‐called ‘sigma receptors’ (sigma1) also known as SR31747A‐binding protein [3,9].…”

“…SR31747A displays immunosuppressive properties [8] that appear to be mediated by the ERG2 ortholog in mammals, namely the subtype 1 of the so‐called ‘sigma receptors’ (sigma1) also known as SR31747A‐binding protein [3,9]. This drug also exhibits anti‐proliferative properties in mammalian cells, that are obtained through the inhibition of the high‐eukaryote‐specific type of Δ8‐Δ7‐sterol isomerase [7]. Finally, inhibition of neuronal cholesterol biosynthesis is thought to induce the long‐term neuroprotective properties exhibited by sterol isomerase ligands [2].…”

Cholesterol biosynthesis from lanosterol: molecular cloning, chromosomal localization, functional expression and liver-specific gene regulation of rat sterol Δ8-isomerase, a cholesterogenic enzyme with multiple functions

“…It is worth noting that SI has three unique features with regard to both enzymic properties and its related diseases (e.g. hypercholesterolaemia, ischaemia and genetic diseases, such as CDP and CHILD syndrome) [13][14][15][16][17][18][19]. First, unlike other cholesterol biosynthesis enzymes, SI does not require any reducing cofactor (i.e.…”