Prevention of diabetes-promoted colorectal cancer by (n-3) polyunsaturated fatty acids and (n-3) PUFA mimetic.

Anna Algamas-Dimantov,Rachel Hertz,Betty Schwartz,Einav Yehuda-Shnaidman,Jacob Bar-Tana,Irena Peri

doi:10.18632/oncotarget.2453

Abstract

The global obesity / diabetes epidemic has resulted in robust increase in the incidence of colorectal cancer (CRC). Epidemiological, animal and human studies have indicated efficacy of (n-3) PUFA in chemoprevention of sporadic and genetic-driven CRC. However, diabetes-promoted CRC presents a treatment challenge that surpasses that of sporadic CRC. This report analyzes the efficacy of (n-3) PUFA generated by the fat-1 transgene that encodes an (n-6) to (n-3) PUFA desaturase, and of synthetic (n-3) PUFA mimetic (MEDICA analog), to suppress CRC development in carcinogen-induced diabetes-promoted animal model. Carcinogen-induced CRC is shown here to be promoted by the diabetes context, in terms of increased aberrant crypt foci (ACF) load, cell proliferation and epithelial dedifferentiation, being accompanied by increase in the expression of HNF4α, β-catenin, and β-catenin-responsive genes. Incorporating the fat-1 transgene in the diabetes context, or oral MEDICA treatment, resulted in ameliorating the diabetic phenotype and in abrogating CRC, with decrease in ACF load, cell proliferation and the expression of HNF-4α, β-catenin, and β-catenin-responsive genes. The specificity of (n-3) PUFA in abrogating CRC development, as contrasted with enhancing CRC by (n-6) PUFA, was similarly verified in CRC cell lines. These findings may indicate prospective therapeutic potential of (n-3) PUFA or MEDICA in the management of CRC, in particular diabetes-promoted CRC.

Highlights

Colorectal cancer (CRC) is the second most common cause of cancer in women and the third most common in men, being the fourth cause of cancer death
The aberrant foci load as well as microadenoma (ACF grade more than 6) of fat-1 mice was robustly decreased compared to C57BL control mice at the two respective time points, implying resistance to CRC development by (n-3) PUFA
In contrast to liver, muscle and adipose tissue where diabetes-induced increase in plasma insulin is compensated by diabetic insulin resistance, insulinsensitive cancer cells in the diabetes context are exposed to high insulin and IGF-1 acting as growth factors

Summary

Introduction

Colorectal cancer (CRC) is the second most common cause of cancer in women and the third most common in men, being the fourth cause of cancer death. Epidemiological studies have indicated variable decrease in sporadic CRC risk (RR 0.67-0.88) upon (n-3) PUFA consumption, with increase in colorectal adenoma risk (RR 1.68) by (n-6) PUFA consumption [5]. These studies were further corroborated by animal studies whereby (n-3) PUFA, administered during the pre- or post-initiation phase, prevented azoxymethane (AOM)- or dimethylhydrazine (DMH)-induced CRC compared with (n-6) PUFA (reviewed in [6] ). (N-3) PUFA efficacy in animal models was further confirmed by reduction in mucosal epithelial cell proliferation index in patients with sporadic colorectal adenoma [11]. Rectal polyp multiplicity and size were significantly reduced by (n-3) PUFA supplementation in patients with Familial adenomatous polyposis (FAP) [12]. (N-3) PUFA efficacy in ameliorating the course of CRC development has been ascribed to modulation of COX activity, disruption of cell surface lipid rafts, increased oxidative stress, and modulation of the activity of specific transcription factors (e.g. HNF-4α, PPARγ/RXR, SREBP1c) (reviewed in [10])

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