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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #362246
Title: Diet supplementation with soy protein isolate, but not the isoflavone genistein, protects against alcohol-induced tumor progression in DEN-treated male mice

Author
item MERCER, K.E. - Arkansas Children'S Nutrition Research Center (ACNC)
item PULLIAM, C.F. - University Arkansas For Medical Sciences (UAMS)
item HENNINGS, L - University Arkansas For Medical Sciences (UAMS)
item CLEVES, M.A. - Arkansas Children'S Nutrition Research Center (ACNC)
item JONES, E.E. - Medical University Of South Carolina
item DRAKE, R.R. - Medical University Of South Carolina
item RONIS, M.J.J. - Louisiana State University Medical Center

Submitted to: Advances in Experimental Medicine and Biology
Publication Type: Book / Chapter
Publication Acceptance Date: 10/16/2018
Publication Date: 10/26/2018
Citation: Mercer, K.E., Pulliam, C.F., Hennings, L., Cleves, M.A., Jones, E.E., Drake, R.R., Ronis, M.J.J. 2018. Diet supplementation with soy protein isolate, but not the isoflavone genistein, protects against alcohol-induced tumor progression in DEN-treated male mice. In: Vasiliou, V., Zakhari, S., Mishra, L., Seitz, H., editors. Alcohol and Cancer. Advances Experimental Medicine and Biology. Vol 1032. Switzerland. Springer Nature. 115-126. https://doi.org/10.1007/978-3-319-98788-0_9.
DOI: https://doi.org/10.1007/978-3-319-98788-0_9

Interpretive Summary: A primary risk factor for liver cancer is chronic alcohol consumption. However, mechanisms by which alcohol promotes carcinogenesis are not well known. Using a mouse model of liver cancer, we show that alcohol increases cell proliferation, resulting in tumorigenesis by enhancing lipid signaling, primary through sphingosine 1-phosphate signaling. Interestingly, mice receiving a soy protein diet while consuming alcohol have less sphingosine-1 phosphate signaling which is associated with decreased tumor burden. These findings show how diet modifications influence cancer risk in high risk populations, i.e. chronic drinkers.

Technical Abstract: Diethylnitrosamine-treated male mice were assigned to 4 groups: a casein-based 35% high fat ethanol liquid diet (EtOH), an EtOH diet made with soy protein isolate protein (EtOH/SOY), an EtOH liquid diet supplemented with genistein (EtOH/GEN) and a chow group. EtOH feeding, final concentration 5% (v/v), continued for 16 wks. EtOH increased incidence and multiplicity of basophilic lesions and adenomas compared to the chow group, (p < 0.05). The EtOH/SOY group had reduced adenoma progression when compared to the EtOH and EtOH/GEN group, (p < 0.05). Genistein supplementation had no protective effect. Soy feeding significantly reduced serum ALT concentrations (p < 0.05), decreased hepatic TNFa and CD-14 expression and decreased nuclear accumulation of NF'B protein in EtOH/SOY-treated mice compared to the EtOH group (p < 0.05). With respect to ceramides, high resolution MALDI-FTICR Imaging mass spectrometry revealed changes in the accumulation of long acyl chain ceramide species, in particular C18, in the EtOH group when compared to the EtOH/SOY group. Additionally, expression of acid ceramidase and sphingosine kinase 1 which degrade ceramide into sphingosine and convert sphingosine to sphingosine-1-phosphate (S1P) respectively and expression of S1P receptors S1PR2 and S1PR3 were all upregulated by EtOH and suppressed in the EtOH/SOY group, p < 0.05. EtOH feeding also increased hepatocyte proliferation and mRNA expression of B-catenin targets, including cyclin D1, MMP7 and glutamine synthase, which were reduced in the EtOH/SOY group, p < 0.05. These findings suggest that soy prevents tumorigenesis by reducing inflammation and by reducing hepatocyte proliferation through inhibition of EtOH-mediated B-catenin signaling. These mechanisms may involve blockade of sphingolipid signaling.