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Functional and Transcriptional Interactions Between Regulator of G‐protein Signaling Protein 10 (RGS10) and Tumor Suppressor Proteins in Cancer Chemosensitization
Author(s) -
Hooks Shelley,
Alqinyah Mohammed,
Webster Andrew,
Sakamuro Daitoku
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.lb496
Subject(s) - ovarian cancer , regulator , histone deacetylase , biology , cancer research , suppressor , cancer , gene , histone , biochemistry , genetics
Ovarian cancer is the deadliest gynecologic cancer, accounting for approximately 15,000 deaths per year. Chemotherapeutic drugs are initially very effective, but more than 80% of patients whose tumors initially respond to chemotherapeutics will relapse within two years with drug‐resistant, terminal disease. Understanding the molecular changes that ovarian cancer cells undergo to gain the ability to survive in the presence of DNA‐damaging chemotherapeutics is critical to develop therapies for chemoresistant cancers. Our studies are focused on the protein Regulator of G‐protein Signaling protein 10 (RGS10), which we have shown is critical in maintaining sensitivity to cisplatin‐induced cell death. Analysis of gene and protein expression in multiple ovarian cancer cell lines demonstrates that expression of RGS10 is suppressed during progression to chemoresistance. Further, we show that acute loss of RGS10 expression directly induces chemoresistance. RGS10 is a nucleo‐cytoplasmic protein with unknown nuclear functions. In order to define the mechanism of RGS10's role in chemoresistance, we probed the functional interaction between RGS10 and the nucleo‐cytoplamic tumor suppressor protein Bridging Integrator 1 protein (BIN1). Our results reveal a functional interaction between RGS10 and BIN1. The ability of BIN1 to regulate cell survival in the presence of cisplatin is partially reversed by normalizing RGS10 expression levels. The mechanism of suppression of RGS10 during chemoresistance is not fully understood, but includes recruitment of histone deacetylase enzymes. To explore upstream signaling that may trigger loss of RGS10 expression, we further determined if there exists an effect of BIN1 expression on RGS10 expression. Our results show that manipulation of BIN1 expression in cancer cells acutely regulates RGS10 expression. Together, our results suggest that the expression and function of RGS10, a novel regulator of ovarian cancer cell survival, is modulated by the established tumor suppressor protein BIN1. Ongoing work will further define the molecular mechanisms linking these two regulator proteins. Support or Funding Information Marsha Rivkin Center for Ovarian Cancer Research (SBH) NCI R01CA140379 (DS)