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Molecular Pharmacology

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Research ArticleArticle

Antiproliferation Activity of a Small Molecule Repressor of Liver Receptor Homolog 1

Cesar A. Corzo, Yelenis Mari, Mi Ra Chang, Tanya Khan, Dana Kuruvilla, Philippe Nuhant, Naresh Kumar, Graham M. West, Derek R. Duckett, William R. Roush and Patrick R. Griffin
Molecular Pharmacology February 2015, 87 (2) 296-304; DOI: https://doi.org/10.1124/mol.114.095554
Cesar A. Corzo
Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida
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Yelenis Mari
Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida
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Mi Ra Chang
Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida
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Tanya Khan
Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida
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Dana Kuruvilla
Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida
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Philippe Nuhant
Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida
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Naresh Kumar
Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida
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Graham M. West
Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida
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Derek R. Duckett
Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida
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William R. Roush
Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida
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Patrick R. Griffin
Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida
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Abstract

The orphan nuclear receptor liver receptor homolog 1 (LRH-1; NR5A2) is a potent regulator of cholesterol metabolism and bile acid homeostasis. Recently, LRH-1 has been shown to play an important role in intestinal inflammation and in the progression of estrogen receptor positive and negative breast cancers and pancreatic cancer. Structural studies have revealed that LRH-1 can bind phospholipids and the dietary phospholipid dilauroylphosphatidylcholine activates LRH-1 activity in rodents. Here we characterize the activity of a novel synthetic nonphospholipid small molecule repressor of LRH-1, SR1848 (6-[4-(3-chlorophenyl)piperazin-1-yl]-3-cyclohexyl-1H-pyrimidine-2,4-dione). In cotransfection studies, SR1848 reduced LRH-1-dependent expression of a reporter gene and in cells that endogenously express LRH-1 dose dependently reduced the expression of cyclin-D1 and -E1, resulting in inhibition of cell proliferation. The cellular effects of SR1848 treatment are recapitulated after transfection of cells with small-interfering RNA targeting LRH-1. Immunocytochemistry analysis shows that SR1848 induces rapid translocation of nuclear LRH-1 to the cytoplasm. Combined, these results suggest that SR1848 is a functional repressor of LRH-1 that impacts expression of genes involved in proliferation in LRH-1–expressing cancers. Thus, SR1848 represents a novel chemical scaffold for the development of therapies targeting malignancies driven by LRH-1.

Footnotes

    • Received September 4, 2014.
    • Accepted December 3, 2014.
  • This work was supported by the National Institutes of Health National Institute of Mental Health [Grant U54-MH074404] and by the National Institutes of Health National Cancer Institute [Grant R01-CA134873].

  • dx.doi.org/10.1124/mol.114.095554.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (2)
Molecular Pharmacology
Vol. 87, Issue 2
1 Feb 2015
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Research ArticleArticle

LRH-1 Repression in Cancer

Cesar A. Corzo, Yelenis Mari, Mi Ra Chang, Tanya Khan, Dana Kuruvilla, Philippe Nuhant, Naresh Kumar, Graham M. West, Derek R. Duckett, William R. Roush and Patrick R. Griffin
Molecular Pharmacology February 1, 2015, 87 (2) 296-304; DOI: https://doi.org/10.1124/mol.114.095554

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Research ArticleArticle

LRH-1 Repression in Cancer

Cesar A. Corzo, Yelenis Mari, Mi Ra Chang, Tanya Khan, Dana Kuruvilla, Philippe Nuhant, Naresh Kumar, Graham M. West, Derek R. Duckett, William R. Roush and Patrick R. Griffin
Molecular Pharmacology February 1, 2015, 87 (2) 296-304; DOI: https://doi.org/10.1124/mol.114.095554
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