Sigma-1 Receptors Bind Cholesterol and Remodel Lipid Rafts in Breast Cancer Cell Lines

Abstract

Lipid rafts are membrane platforms that spatially organize molecules for specific signaling pathways that regulate various cellular functions. Cholesterol is critical for liquidordered raft formation by serving as a spacer between the hydrocarbon chains of sphingolipids, and alterations in the cholesterol contents of the plasma membrane causes disruption of rafts. The role that S receptors play in cancer is not clear, although it is frequently up-regulated in human cancer cells and tissues and S receptors inhibit proliferation in carcinoma and melanoma cell lines, induce apoptosis in colon and mammary carcinoma cell lines, and reduce cellular adhesion in mammary carcinoma cell lines. In this study, we provide molecular and functional evidence for the involvement of the enigmatic S1 receptors in lipid raft modeling by S1 receptor-mediated cholesterol alteration of lipid rafts in breast cancer cell lines. Cholesterol binds to cholesterol recognition domains in the COOH terminus of the S1 receptor. This binding is blocked by S receptor drugs because the cholesterol-binding domains form part of the S receptor drugbinding site, mutations of which abolish cholesterol binding. Furthermore, we outline a hypothetical functional model to explain the myriad of biological processes, including cancer, in which these mysterious receptors are involved. The findings of this study provide a biological basis for the potential therapeutic applications of lipid raft cholesterol regulation in cancer therapy using S receptor drugs. [Cancer Res 2007; 67(23):11166-75]

Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

“…The purified antibody concentration was 378.6 μg/ml. Production of the sigma-1 receptor antibody in rabbits was described previously (Palmer et al 2007). …”

“…The protein has two transmembrane regions and two steroid-binding domains. The latter forms a pocket that serves as a binding site for cholesterol, steroids and sphingolipids (Palmer et al 2007;Fontanilla et al 2009). A wide range of synthetic or natural compounds ('sigma ligands'), including opiates, antipsychotics, psychostimulants, alkaloids and antidepressants, also bind to sigma-1 receptors (Palmer et al 2008;Maurice and Su 2009).…”

“…The most in-depth study on the role that sigma-1 receptors play in BCa was performed by Palmer et al (2007). The results indicated that cancer cells express high levels of sigma-1 receptors compared with corresponding normal cells.…”

“…Localisation of the sigma-1 receptor was investigated in MDA-MB-231 cells by immunocytochemistry and confocal microscopy. Expression was predominantly at the cell periphery but also in the endoplasmic reticulum (Palmer et al 2007). Both sigma-1 and sigma-2 drugs and a sigma-1 receptor silencing construct reduced proliferation and adhesion of BCa cell lines compared to a non-cancerous BCa cell line.…”

“…Both sigma-1 and sigma-2 drugs and a sigma-1 receptor silencing construct reduced proliferation and adhesion of BCa cell lines compared to a non-cancerous BCa cell line. The effect on adhesion was found to be through a functional interaction with β-1 integrin (Palmer et al 2007). Although the exact nature of how sigma-1 receptors could modulate adhesion and migration in BCa cells has not been determined, it has been suggested that voltage-gated sodium channels (VGSCs) known to be expressed in BCa cells could play an important role (Aydar et al 2004).…”