Abstract POSTER-BIOL-1343: Peroxisome proliferator-activated receptor-gamma (PPAR-γ) prevents ovarian cancer progression

Abstract

Abstract Background: The lack of information on the molecular etiology associated with ovarian malignant transformation hinders the prevention of ovarian cancer (OVCA) as well as its early detection. Longstanding unresolved chronic inflammation has been suggested as a risk factor for carcinogenesis. Ovarian surface epithelium (site of ovulatory rupture) and fimbrial surface epithelium (site of receiving of ovulated ovum) are exposed to inflammatory agents due to ovulation as well as ovarian autoimmune conditions. Sustained exposure to chronic inflammation leads to the inactivation of PPAR-γ, a member of steroid receptor superfamily. PPAR-γ has been shown to be tumor suppressive in several malignancies. However, systematic studies on the role of PPAR-γ in OVCA development and progression have not been performed. Herbs are used in traditional medicine as anti-tumor agents. The herb Ashwagandha (Withania somnifera, ASH), has long been used as anti-inflammatory and anti-oxidant in traditional medicine. However, its role in prevention of OVCA-associated change in PPAR-γ function is not known. Objective: The goals of this study were to determine (i) if PPAR-γ expression changes in association with OVCA development and progression and (ii) if dietary supplementation of ASH enhances PPAR-γ expression in laying hens, a preclinical model of spontaneous OVCA. Materials and Methods: Changes in PPAR-γ expression in association with OVCA development and progression were determined in an exploratory study by immunohistochemistry (IHC), gene expression, and proteomic studies using normal ovaries (n=10) and ovaries with cancer at early (n=7) and late stages (n= 20) of OVCA. In the prospective study, hens with or without early stage OVCA were selected by ultrasound scanning and grouped into control (basal diet), 1% and 2% ASH root powder supplemented diet. 30 hens (25 healthy, 5 with early stage OVCA) were grouped in each dietary category. Hens were provided with feed and water ad libitum and maintained for 90 days. At the end of 90-days, hens were euthanized, normal and cancerous ovaries were processed for PPAR-γ expression as mentioned above. Results: Compared with early stage OVCA, the expression of PPAR-γ was significantly lower in approximately 75% of OVCA cases at late stages. This decrease in tissue expression of PPAR-γ was associated with decreased in gene expression. Furthermore, decreased PPAR-γ expression was more pronounced in poorly differentiated tumors than well differentiated ones. In the prospective study, compared with control and 1%, OVCA incidences and tumor metastasis were reduced markedly in hens supplemented with 2% dietary ASH. Reduction in OVCA incidence and progression was associated with the increased expression of PPAR-γ in the tumor tissues. ASH treatment enhanced gene expression of PPAR-γ in hens supplemented with 2% ASH. Conclusion: The expression of PPAR-γ was inversely associated with ovarian tumor development and progression. Dietary supplementation of ASH increased the expression of PPAR-γ significantly and reduced the incidence of OVCA as well as its metastasis. These results will form a foundation for a clinical study. Support: Dept. of Defense award # W81XWH-12-1-0460. Citation Format: Lauren E. Rosen, Animesh Barua, Janice M Bahr, Sanjib Basu, Sameer Sharma, Seby E Edassery, Alfred S Guirguis, Pincas Bitterman. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) prevents ovarian cancer progression [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1343.