Premium
Regulator of G‐Protein Signaling 2 Blunts Cellular Viability Mediated By A Stabilized Lysophosphatidic Acid Analogue In the Presence of Chemotherapy In An Ovarian Cancer Cell Model of Chemoresistance
Author(s) -
Altman Molly Koertel,
Callihan Phillip,
Ali Mourad,
Hooks Shelley,
Murph Mandi
Publication year - 2012
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.26.1_supplement.838.1
Subject(s) - lysophosphatidic acid , viability assay , g protein coupled receptor , regulator of g protein signaling , receptor , signal transduction , biology , cancer research , ovarian cancer , g protein , microbiology and biotechnology , cancer cell , cell growth , cell , chemistry , cancer , biochemistry , gtpase activating protein , genetics
Lysophosphatidic acid (LPA) enhances growth, survival, and proliferation in numerous models. The receptors for LPA are implicated in oncogenic signaling and represent a group of therapeutic targets in cancer. Regulator of G protein Signaling 2 (RGS2) is a GTPase activating protein (GAP) that turns off G protein‐coupled receptor (GPCR) signaling. Previously, we demonstrated that reduced RGS gene expression develops with the occurrence of drug resistance in ovarian cancer cell lines. Here, we investigate whether the LPA receptors are also involved in mediating viability as a result of enhanced GPCR signaling. To test this idea we used the metabolically stabilized LPA analogue L‐sn‐ 1‐O‐oleoyl‐2‐O‐methylglyceryl‐3‐phosphothionate (2S‐OMPT) as a potent agonist for LPA receptors at a concentration (10 μM) sufficient to activate multiple LPA receptors. We hypothesized that if LPA signaling was not involved, then OMPT would override any contribution of RGS2 on modulating the viability response in the presence of chemotherapy. We generated an inducible stable model of RGS2‐expressing HeyA8‐MDR cells. After 48 h OMPT pre‐treatment, HeyA8‐MDR‐RGS2‐inducible cells were exposed to cisplatin for 24 h and evaluated for viability. All conditions pretreated with OMPT demonstrated enhanced viability even in the presence of chemotherapy; however, ovarian cancer cells that were pretreated with OMPT and cultured in tet‐free medium to induce RGS2 expression showed a significant blunting of viability. Research funded by the NCI, NIH, and GCC.