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Effects of LRH‐1 Antagonism on Pancreatic Adenocarcinoma Cells
Author(s) -
Kothari Devraj,
RondonOrtiz Alejandro,
Mendigure Ana,
PinoFigueroa Alejandro
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1194.6
Subject(s) - viability assay , apoptosis , trypan blue , pancreatic cancer , antagonist , chemistry , cell growth , endocrinology , medicine , pancreas , receptor antagonist , cancer research , receptor , biology , cancer , biochemistry
Pancreatic cancer accounts for nearly 3% of all cancers in the U.S. and about 7% of deaths associated with cancer. Liver receptor homolog‐1 (LRH‐1) is an orphan nuclear receptor previously linked to pancreas development and pancreatic adenocarcinoma. It is predominantly present in exocrine pancreas, liver, breast and gastrointestinal tissues. LRH‐1 also regulates the transcriptional targets responsible for controlling cell growth, differentiation, and proliferation. Upregulation of LRH‐1 may be linked to a more aggressive, metastatic form of cancer. The objective of this study was to determine and characterize the in vitro inhibitory effect(s) of 1‐(3′‐(1‐(2‐Morpholinoethyl)‐1H‐pyrazol‐3‐yl)biphenyl‐3‐yl)ethanone (LRH‐1 receptor antagonist) on pancreatic adenocarcinoma (AsPC‐1 cells). The drug antiproliferative effect was tested using a cell viability screening assay method. AsPC‐1 cells were cultured in a 96‐well plate using RPMI‐1640 media and 10% FBS. Cells were exposed to antagonist from 0.1 to 100 μM. Cell viability was determined 24 hours later by trypan blue exclusion and/or the dimethylthiazolyl‐carboxymethoxyphenyl‐sulfophenyl‐tetrazolium (MTS) viability assays. The effect on Caspase activity was determined after exposing the cells to 1.5 and 10 μM of LRH‐1 antagonist. The results demonstrated that LRH‐1 antagonist possessed significant (p<0.05) concentration‐dependent antitumoral activity with a 31% maximum reduction in cell viability and 38% maximum increase of Caspase‐3/7 activity. Biomarkers, such as cyclin D1, E1, and Bcl‐xl, were also measured pre‐ and post‐treatment using western blotting assay methods. Gemcitabine was compared to LRH‐1 antagonist alone and in combination to assess for possible synergistic effects. The results suggest a potential application of LRH‐1 antagonist to better understand the involvement of LRH‐1receptor in the development and progression of cancer. This drug was shown to influence proliferation and apoptotic activity in pancreatic adenocarcinoma cells. LRH‐1 antagonist could be used as a primary compound to design selective and potent LRH‐1 blockers that could be used clinically as therapeutic agents towards pancreatic or other cancers.