Maslinic acid-enriched diet decreases intestinal tumorigenesis in Apc(Min/+) mice through transcriptomic and metabolomic reprogramming - PubMed (original) (raw)

Maslinic acid-enriched diet decreases intestinal tumorigenesis in Apc(Min/+) mice through transcriptomic and metabolomic reprogramming

Susana Sánchez-Tena et al. PLoS One. 2013.

Abstract

Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancer-related death in western countries. In this regard, maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in Apc(Min/+) mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid-supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P<0.01). Putative molecular mechanisms associated with suppressing intestinal polyposis in Apc(Min/+) mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the Apc(Min/+) mice model, suggesting its chemopreventive potential against colorectal cancer.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Body weight and diet consumption monitoring.

A) Effects of MA treatment on body weight. B) Effects of MA feeding in food intake. Data represented as mean ± SEM (* *, p<0.01).

Figure 2

Figure 2. MA feeding inhibits intestinal polyposis in APCMin/+ mice.

A) Total number of polyps/mouse in the small intestine of ApcMin/+ mice. B) Number of polyps/mouse in proximal, medial and distal sections. C) Number of polyps/mouse shown by polyp size distribution (<1 mm diameter polyps, 1–2 mm and >2 mm). Data represented as mean ± SEM (* *, p<0.01).

Figure 3

Figure 3. Adaptation of KEGG colorectal cancer pathway using KEGG Mapper.

Circular pathway members were significantly up-regulated and rectangular members were found to be down-regulated in the intestinal mucosa of ApcMin/+ mice treated with MA. Horizontal lines indicate a fold change (FC) of between 1.5 and 2 and vertical lines a FC of more than 2.

Figure 4

Figure 4. Validation of genes that were differentially expressed in the colon mucosa of ApcMin/+ mice after MA treatment by RT-PCR.

Mean ± SD are shown. *, p<0.05; * *, **p<0.01, versus the untreated condition. n = 8/group.

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Grants and funding

Financial support was provided by grant SAF2011-25726 and personal financial support (FPU program) from the Spanish government and also from the Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation & European Regional Development Fund “Una manera de hacer Europa” (ISCIII-RTICC grants RD06/0020/004 and RD06/0020/1019 and BIO2011-27069, MICINN). The authors have also received financial support from the AGAUR-Generalitat de Catalunya (grant 2009SGR1308, 2009 CTP 00026 and Icrea Academia Award 2010 granted to M.C.) and the European Commission (FP7) ETHERPATHS KBBE-grant agreement no. 22263. The authors thank the Bio-NMR EU project (Contract # 261863) for providing NMR access to the HWB-NMR facility. Finally, the authors are grateful for the financial support from Biomaslinic S.L. (Granada, Spain). Biomaslinic also supplied the Maslinic Acid required for the investigation purpose. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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