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Sigma Receptor Antagonists Inhibit Human Lens Cell Growth and Induce Pigmentation

¹From the School of Biological Sciences, University of East Anglia, Norwich, United Kingdom; the ²Centre for High-Resolution Imaging (CHIPs), School of Life Sciences, and the ³Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.

PURPOSE. The expression of the Sigma 1 receptor and the ability of receptor antagonists to inhibit growth and induce pigment formation were investigated in human lens epithelial cells.

METHODS. Capsular bags were formed for experimental purposes by performing sham cataract operations on donor lenses. The resultant bags were cultured in Eagle’s minimum essential medium (EMEM) alone or supplemented with the Sigma receptor antagonists rimcazole (3 µM) and BD1047 (10 µM). Cell growth was monitored by phase microscopy. Tyrosine incorporation was quantified by culturing in the presence of 14-C tyrosine for 24 hours. At the end of the culture period, some bags were fixed in 4% paraformaldehyde for electron microscopy, and others were plunged into liquid nitrogen for later immunoblot and PCR analyses. Protein levels of tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and tyrosinase-related protein 2 (TYRP2) were quantified by Western blot analysis. The presence of pigment granules within epithelial cells were monitored by phase and electron microscopy techniques.

RESULTS. The Sigma-1 receptor was expressed in native human lens cells and in cultured capsular bag cells. The Sigma receptor antagonists BD1047 and rimcazole inhibited lens cell growth and, surprisingly, lens cells accumulated pigment granules in the presence of the antagonists. The antagonists raised preexisting levels of TYR and TYRP1, whereas there was no change in TYRP2.

CONCLUSIONS. The human lens normally expresses components of the melanin synthesis pathway, and this suggests a possible origin for the pigment granules that have been observed under certain conditions in the human lens. Exposure of lens cells to Sigma receptor antagonists leads to growth inhibition and pigment granule production.

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