Xanthophyll beta-cryptoxanthin inhibits highly refined carbohydrate diet-promoted hepatocellular carcinoma progression in mice

Authors: LIM, JI YE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HU, KANG-QUAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SMITH, DONALD - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LAMON-FAVA, STEFANIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; AUSMAN, LYNNE - Tufts University; WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Molecular Nutrition and Food Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/10/2019
Publication Date: 12/31/2019
Citation: Lim, J., Liu, C., Hu, K., Smith, D.E., Wu, D., Lamon-Fava, S., Ausman, L.M., Wang, X. 2019. Xanthophyll beta-cryptoxanthin inhibits highly refined carbohydrate diet-promoted hepatocellular carcinoma progression in mice. Molecular Nutrition and Food Research. 64(3):e1900949. https://doi.org/10.1002/mnfr.201900949.
DOI: https://doi.org/10.1002/mnfr.201900949

Interpretive Summary: We examined whether beta-cryptoxanthin (BCX, a provitamin A carotenoid rich in sweet red pepper) feeding could inhibit high-refined carbohydrate/sugar diet (HRCD)-promoted liver cancer development in a mouse model. We found that mice fed BCX had significantly lower liver cancer multiplicity, average tumor size, and total tumor volume, in both presence and absence of carotenoid breakdown enzymes (BCO1/BCO2 which convert BCX into vitamin A). This study suggests that BCX feeding may alleviate HRCD-promoted liver cancer progression.

Technical Abstract: Scope: Beta-Cryptoxanthin (BCX), a provitamin A carotenoid, can be cleaved by both beta-carotene 15,15'-oxygenase (BCO1) and beta-carotene 9',10'-oxygenase (BCO2) generating biological active vitamin A and apocarotenoids. The aim of this study was to determine whether BCX feeding could inhibit diethylnitrosamine (DEN)-initiated, high-refined carbohydrate diet (HRCD)-promoted hepatocellular carcinoma (HCC) development, dependent or independent of BCO1/BCO2 activity. Methods and Results: Two-week-old male wild-type (WT) and BCO1-/-/BCO2-/- double knock-out (DKO) mice were given a single intraperitoneal injection of DEN (25 mg/kg body weight) to initiate hepatic carcinogenesis. At six weeks of age, all animals were fed HRCD (66.5 % of energy from carbohydrate) with or without BCX for 24 weeks. BCX feeding increased hepatic vitamin A levels in WT mice, but not in DKO mice that showed a significant accumulation of hepatic BCX. Compared to their respective HRCD littermates, both WT and DKO fed BCX had significantly lower HCC multiplicity (58-60%), average tumor size (21-24%), and total tumor volume (51-58%), and the steatosis scores. The chemopreventive effects of BCX were associated with increased p53 protein acetylation and gluconeogenesis markers (phosphoenolpyruvate carboxykinase, glucose 6-phosphatase) and decreased protein levels of a glycolysis marker (lactate dehydrogenase) and of the hypoxia-inducible factor-1alpha and its downstream targets, matrix metalloproteinase 2/9 in tumors. Conclusions: This study suggests that BCX feeding may alleviate HRCD-promoted HCC progression by modulating the acetylation of p53, hypoxic tumor microenvironment and glucose metabolism, independent of BCO1 and BCO2.