Metabolic Regulation of Glycolysis and AMP Activated Protein Kinase Pathways during Black Raspberry-Mediated Oral Cancer Chemoprevention
Thomas J. Knobloch,
Nathan M. Ryan,
Lei Bruschweiler-Li,
Cheng Wang,
Matthew C. Bernier,
Arpad Somogyi,
Pearlly S. Yan,
Jessica L. Cooperstone,
Xiaokui Mo,
Rafael P. Brüschweiler,
Christopher M. Weghorst,
Steve Oghumu
Affiliations
Thomas J. Knobloch
Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH 43210, USA
Nathan M. Ryan
Department of Pathology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Lei Bruschweiler-Li
Department of Chemistry and Biochemistry, College of Arts and Sciences, The Ohio State University, Columbus Ohio, Columbus, OH 43210, USA
Cheng Wang
Department of Chemistry and Biochemistry, College of Arts and Sciences, The Ohio State University, Columbus Ohio, Columbus, OH 43210, USA
Matthew C. Bernier
Campus Chemical Instrument Center, Mass Spectrometry and Proteomics Facility, The Ohio State University, Columbus, OH 43210, USA
Arpad Somogyi
Campus Chemical Instrument Center, Mass Spectrometry and Proteomics Facility, The Ohio State University, Columbus, OH 43210, USA
Pearlly S. Yan
Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
Jessica L. Cooperstone
Department of Horticulture and Crop Science, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Columbus, OH 43210, USA
Xiaokui Mo
Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
Rafael P. Brüschweiler
Department of Chemistry and Biochemistry, College of Arts and Sciences, The Ohio State University, Columbus Ohio, Columbus, OH 43210, USA
Christopher M. Weghorst
Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH 43210, USA
Steve Oghumu
Department of Pathology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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.
