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Metabolic Regulation of Glycolysis and AMP Activated Protein Kinase Pathways during Black Raspberry-Mediated Oral Cancer Chemoprevention

1
Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH 43210, USA
2
Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
3
Department of Pathology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
4
Department of Chemistry and Biochemistry, College of Arts and Sciences, The Ohio State University, Columbus Ohio, Columbus, OH 43210, USA
5
Campus Chemical Instrument Center, Mass Spectrometry and Proteomics Facility, The Ohio State University, Columbus, OH 43210, USA
6
Department of Horticulture and Crop Science, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Columbus, OH 43210, USA
7
Department of Food Science and Technology, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Columbus, OH 43210, USA
8
Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
*
Author to whom correspondence should be addressed.
Metabolites 2019, 9(7), 140; https://doi.org/10.3390/metabo9070140
Received: 29 May 2019 / Revised: 15 June 2019 / Accepted: 8 July 2019 / Published: 11 July 2019
(This article belongs to the Special Issue Plant, Food and Nutritional Metabolomics for Health Enhancement)
Oral cancer is a public health problem with an incidence of almost 50,000 and a mortality of 10,000 each year in the USA alone. Black raspberries (BRBs) have been shown to inhibit oral carcinogenesis in several preclinical models, but our understanding of how BRB phytochemicals affect the metabolic pathways during oral carcinogenesis remains incomplete. We used a well-established rat oral cancer model to determine potential metabolic pathways impacted by BRBs during oral carcinogenesis. F344 rats were exposed to the oral carcinogen 4-nitroquinoline-1-oxide in drinking water for 14 weeks, then regular drinking water for six weeks. Carcinogen exposed rats were fed a 5% or 10% BRB supplemented diet or control diet for six weeks after carcinogen exposure. RNA-Seq transcriptome analysis on rat tongue, and mass spectrometry and NMR metabolomics analysis on rat urine were performed. We tentatively identified 57 differentially or uniquely expressed metabolites and over 662 modulated genes in rats being fed with BRB. Glycolysis and AMPK pathways were modulated during BRB-mediated oral cancer chemoprevention. Glycolytic enzymes Aldoa, Hk2, Tpi1, Pgam2, Pfkl, and Pkm2 as well as the PKA-AMPK pathway genes Prkaa2, Pde4a, Pde10a, Ywhag, and Crebbp were downregulated by BRBs during oral cancer chemoprevention. Furthermore, the glycolysis metabolite glucose-6-phosphate decreased in BRB-administered rats. Our data reveal the novel metabolic pathways modulated by BRB phytochemicals that can be targeted during the chemoprevention of oral cancer. View Full-Text
Keywords: HNSCC; metabolomics; transcriptomics; black raspberries; oral cancer; chemoprevention HNSCC; metabolomics; transcriptomics; black raspberries; oral cancer; chemoprevention
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Knobloch, T.J.; Ryan, N.M.; Bruschweiler-Li, L.; Wang, C.; Bernier, M.C.; Somogyi, A.; Yan, P.S.; Cooperstone, J.L.; Mo, X.; Brüschweiler, R.P.; Weghorst, C.M.; Oghumu, S. Metabolic Regulation of Glycolysis and AMP Activated Protein Kinase Pathways during Black Raspberry-Mediated Oral Cancer Chemoprevention. Metabolites 2019, 9, 140.

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