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The G Protein-Coupled Receptor GPR30 Inhibits Human Urothelial Cell Proliferation

Department of Surgical Sciences (J.T., Z.-Y.W., D.E.B.), School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706; Department of Cell Biology & Physiology (E.R.P.), Cancer Research and Treatment Center (E.R.P.), University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131; and Division of Urology (D.E.B.), Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin 53792

Address all correspondence and requests for reprints to: Dale E. Bjorling, Department of Surgical Sciences, School of Veterinary Medicine, 2015 Linden Drive, Madison, Wisconsin 53706. E-mail: bjorlind{at}svm.vetmed.wisc.edu.

We have previously shown that estrogen stimulates cell proliferation in both normal and transformed urothelial cells mainly through activation of the two primary estrogen receptors (ERs), ER and ERβ. A growing body of evidence suggests that estrogen also initiates nongenomic effects that cannot be explained by activation of primary ERs. In the present study, we observed that urothelial cells express high amounts of GPR30, a G protein-coupled receptor recently identified as a candidate for membrane-associated estrogen binding. Membrane- impermeable bovine serum albumin-conjugated 17β-estradiol and the specific GPR30 agonist G-1 both inhibited urothelial cell proliferation in a concentration-dependent manner. Transient overexpression of GPR30 inhibited 17β-estradiol (E2)-induced cell proliferation. Decreased GPR30 expression caused by specific small interfering RNA increased E2-induced cell proliferation. These results indicate that membrane-associated inhibitory effects of E2 on cell proliferation correlate with abundance of GPR30. Although E2 induced a significant increase in caspase-3/7 activity, G-1 did not, suggesting that the GPR30-mediated inhibitory effect on cell proliferation was not caused by apoptosis. Furthermore, we found that G-1 failed to induce c-fos, c-jun, and cyclin D1 expression, and GPR30 overexpression abolished E2-induced c-fos, c-jun, and cyclin D1 expression. However, inactivation of GPR30 by small interfering RNA increased c-fos, c-jun, and cyclin D1 expression. These results suggest that GPR30-mediated inhibition of urothelial cell proliferation is the result of decreased cyclin D1 by down-regulation of activation protein-1 signaling.

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