S2R ^Pgrmc1: The cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling

Introduction: S2R (sigma-2 receptor)/Pgrmc1 (progesterone receptor membrane component 1) is a cytochrome-related protein that binds directly to heme and various pharmacological compounds. S2R ^Pgrmc1 also associates with cytochrome P450 proteins, the EGFR receptor tyrosine kinase and the RNA-binding protein PAIR-BP1. S2R ^Pgrmc1 is induced in multiple types of cancer, where it regulates tumor growth and is implicated in progesterone signaling. S2R ^Pgrmc1 also increases cholesterol synthesis in non-cancerous cells and may have a role in modulating drug metabolizing P450 proteins. Areas covered: This review covers the independent identification of S2R and Pgrmc1 and their induction in cancers, as well as the role of S2R ^Pgrmc1 in increasing cholesterol metabolism and P450 activity. This article was formed through a PubMed literature search using, but not limited to, the terms sigma-2 receptor, Pgrmc1, Dap1, cholesterol and aromatase. Expert opinion: Multiple laboratories have shown that S2R ^Pgrmc1 associates with various P450 proteins and increases cholesterol synthesis via Cyp51. However, the lipogenic role of S2R ^Pgrmc1 is tissue-specific. Furthermore, the role of S2R ^Pgrmc1 in regulating P450 proteins other than Cyp51 appears to be highly selective, with modest inhibitory activity for Cyp3A4 in vitro and a complex regulatory pattern for Cyp21. Cyp19/aromatase is a therapeutic target in breast cancer, and S2R ^Pgrmc1 activated Cyp19 significantly in vitro but modestly in biochemical assays. In summary, S2R ^Pgrmc1 is a promising therapeutic target for cancer and possibly cholesterol synthesis but research to date has not identified a major role in P450-mediated drug metabolism.