Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice.

Abstract

Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10'-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9',10'-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)-promoted liver inflammation, and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 expression is important using BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs. 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs. 20%) and multiplicity (58% vs. 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic proinflammatory signaling (phosphorylation of NK-κB p65 and STAT3; IL6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress-mediated unfolded protein response (ER(UPR)), through decreasing ER(UPR)-mediated protein kinase RNA-activated like kinase-eukaryotic initiation factor 2α activation, and inositol requiring 1α-X-box-binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals, including Met mRNA, β-catenin protein, and mTOR complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression.

• Authors: Blanche C Ip, Chun Liu, Lynne M Ausman, Johannes von Lintig, Xiang-Dong Wang
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 7 Issue 12 Pg. 1219-27 (Dec 2014) ISSN: 1940-6215 [Electronic] United States
• PMID: 25293877 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Anticarcinogenic Agents
• RNA, Messenger
• Carotenoids
• Dioxygenases
• Bco2 protein, mouse
• Lycopene

Topics

• Animals
• Anticarcinogenic Agents (administration & dosage)
• Blotting, Western
• Carcinoma, Hepatocellular (metabolism, pathology, prevention & control)
• Carotenoids (administration & dosage)
• Cell Transformation, Neoplastic
• Diet, High-Fat
• Dietary Supplements
• Dioxygenases (physiology)
• Endoplasmic Reticulum Stress (drug effects)
• Humans
• Immunoenzyme Techniques
• Liver Neoplasms (metabolism, pathology, prevention & control)
• Lycopene
• Male
• Mice
• Mice, Knockout
• Phosphorylation (drug effects)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Tumor Cells, Cultured