Abstract
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.
Highlights
Oral cancer is estimated to cause almost 50,000 new cases and nearly 10,000 deaths this year in the US alone [1]
Given that glucose metabolism is partly regulated by the serine threonine protein kinase AMPactivated protein kinase (AMPK) [27], we investigated the impact of BRB administration on the signaling pathways associated with this essential metabolic regulator as well as the related protein kinase A (PKA)
Our metabolomic and transcriptomic data revealed a number of novel metabolic pathways modulated by BRB as well as the altered transcriptional profile associated with these modulated pathways as a result of BRB-mediated chemoprevention during oral carcinogenesis
Summary
Oral cancer is estimated to cause almost 50,000 new cases and nearly 10,000 deaths this year in the US alone [1]. We analyzed the total gene expression using RNA-Seq of rat tongue tissue from BRB fed and These oral cancer-associated pathways included genes involved in cancer development, cell cycle regulation, MAP kinase signaling, leukocyte extravasation, and DNA repair, which were regulated in a manner that supports a cancer preventive role for BRB during oral carcinogenesis (Figure 2B). An integrated analysis of transcriptomic and metabolomic data by IPA and MetaboAnalyst revealed a significant modulation of genes and metabolites associated with the glycolytic pathway (Figure 3 and Table 1) This is significant because enhanced glucose fermentation even in the presence of oxygen and functioning mitochondria, known as the Warburg effect, is a major metabolic mechanism used by cancer cells to promote proliferation and survival, and targets of this pathway are being developed for cancer therapy [25,26].
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