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Subcellular Localization of Sigma-2 Receptors in Breast Cancer Cells Using Two-Photon and Confocal Microscopy

¹ Department of Radiology, Division of Radiological Sciences, ² Department of Cell Biology and Physiology, and ³ Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri; ⁴ Department of Radiology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, North Carolina; and ⁵ Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Robert H. Mach, Division of Radiological Sciences, Washington University School of Medicine, Campus Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO 63110. Phone: 314-362-8538; Fax: 314-362-0039; E-mail: rhmach{at}mir.wustl.edu.

Sigma-2 receptor agonists have been shown to induce cell death via caspase-dependent and caspase-independent pathways. Unfortunately, there is little information regarding the molecular function of sigma-2 receptors that can explain these results. In this study, two fluorescent probes, SW107 and K05-138, were used to study the subcellular localization of sigma-2 receptors by two-photon and confocal microscopy. The results indicate that sigma-2 receptors colocalize with fluorescent markers of mitochondria, lysosomes, endoplasmic reticulum, and the plasma membrane in both EMT-6 mouse and MDA-MB-435 human breast cancer cells. The fluorescent probe, K05-138, was internalized rapidly, reaching a plateau of fluorescent intensity at 5 min. The internalization of K05-138 was reduced 40% by phenylarsine oxide, an inhibitor of endocytosis. These data suggest that sigma-2 ligands are internalized, in part, by an endocytotic pathway. The localization of sigma-2 receptors in several organelles known to have a role in both caspase-dependent and caspase-independent pathways of cell death supports the conclusions of previous studies suggesting that sigma-2 receptor ligands should be evaluated as potential cancer chemotherapeutic agents. [Cancer Res 2007;67(14):6708–16]

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