Elevation of ω-3 Polyunsaturated Fatty Acids Attenuates PTEN-deficiency Induced Endometrial Cancer Development through Regulation of COX-2 and PGE2 Production.

Jinshun Pan,Xiaoming Bai,Allan Z Zhao,Xin Zhang,Fanghong Li,Xinyun Bi,Shanshan Liu,Lixian Cheng

doi:10.1038/srep14958

Jinshun Pan, Xiaoming Bai + Show 6 more

Open Access

https://doi.org/10.1038/srep14958

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Journal: Scientific Reports	Publication Date: Oct 15, 2015
Citations: 24	License type: CC BY 4.0

Affiliation: Nanjing Medical University

Abstract

Endometrial cancer is one of the most common gynecologic malignancies. Phosphatase and tensin homologue (PTEN)-mutation is frequently identified in endometrial cancer patients. Although high dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) has been associated with reduced risk of endometrial cancer, the underlying mechanisms is still unknown. To this end, we evaluated the impact of ω-3 PUFAs using several endometrial cancer cellular and animal models. While ~27% and 40% of heterozygotic PTEN mutant mice developed endometrial cancer and atypical complex hyperplasia, respectively, none of the PTEN+/− mice developed cancer when we overexpressed an mfat-1 transgene, which allowed endogenous production of ω-3 PUFAs. Fish oil-enriched diet or expression of mfat-1 transgene significantly inhibited the growth of xenograft tumor derived from RL95-2 cells bearing a PTEN null mutation. At cellular level, ω-3 PUFAs treatment decreased the viability of RL95-2 cells, AKT phosphorylation, and cyclin D1 expression. These molecular events are primarily mediated through reduction of cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Exogenous PGE2 treatment completely blunted the impact of ω-3 PUFAs on endometrial cancer. Thus, we revealed the direct inhibitory effects of ω-3 PUFAs on endometrial cancer development and the underlying mechanisms involving reduction of COX-2 and PGE2.

Highlights

The Phosphatase and tensin homologue (PTEN) gene is located on chromosome 10q23, a genomic region that suffers loss of heterozygosity in many human cancers
Analysis of fatty acid compositions confirms the activity of mfat-1 protein, with a significant decrease in arachidonic acid (AA), a concomitant increase in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels, and a significantly decreased ratio of ω -6/ω -3 polyunsaturated fatty acids (PUFAs) compared with the mice lacking mfat-1 expression (PTEN+/+, PTEN+/−) (Table 1)
These results suggest that elevated tissue levels of ω -3 PUFAs suppress PTEN-deficiency induced endometrial cancer development

Summary

Introduction

The PTEN gene is located on chromosome 10q23, a genomic region that suffers loss of heterozygosity in many human cancers. We previously reported a transgenic mouse model overexpressing a C. elegans gene, mfat-1, encoding an ω -3 fatty acid desaturase[20] This enzyme can produce ω -3 PUFAs endogenously by converting ω -6 to ω -3 PUFAs, which enables the investigation of the biological properties of ω -3 PUFAs without the need of lengthy feeding of fish oil. This model makes it possible to use genetic approach by, for example, crossing the mfat-1 transgenics with the haploid PTEN-deficient mice. The potential positive outcomes of our studies may benefit the patients with PTEN-deficient endometrial cancer

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