More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations, and are often refractory to approved targeted therapies. We report that cultured CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C depleting glutathione. Thus, ROS accumulates and inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibiting GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells. In vivo studies indicate that high-dose vitamin C can impair tumor growth in Apc/KrasG12D mutant mouse intestinal cancers. While it is unclear whether human tumors will respond similarly, our results provide a mechanistic rationale for exploring the therapeutic use of vitamin C to treat CRCs with KRAS or BRAF mutations.

Excessive consumption of beverages sweetened with high-fructose corn syrup (HFCS) is associated with obesity and with an increased risk of colorectal cancer. Whether HFCS contributes directly to tumorigenesis is unclear. We investigated the effects of daily oral administration of HFCS in adenomatous polyposis coli (APC) mutant mice, which are predisposed to develop intestinal tumors. The HFCS-treated mice showed a substantial increase in tumor size and tumor grade in the absence of obesity and metabolic syndrome. HFCS increased the concentrations of fructose and glucose in the intestinal lumen and serum, respectively, and the tumors transported both sugars. Within the tumors, fructose was converted to fructose-1-phosphate, leading to activation of glycolysis and increased synthesis of fatty acids that support tumor growth. These mouse studies support the hypothesis that the combination of dietary glucose and fructose, even at a moderate dose, can enhance tumorigenesis.

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Background: Ethanol (EtOH) is a teratogen that causes severe birth defects, but the mechanisms by which EtOH affects stem cell differentiation are unclear. Our goal here is to examine the effects of EtOH and its metabolites, acetaldehyde (AcH) and acetate, on embryonic stem cell (ESC) differentiation.Methods: We designed ESC lines in which aldehyde dehydrogenase (ALDH2, NCBI#11669) and acyl-CoA synthetase short-chain family member 2 (ACSS2, NCBI#60525) were knocked out by CRISPR-Cas9 technology. We selected these genes because of their key roles in EtOH oxidation in order to dissect the effects of EtOH metabolism on differentiation.Results: By using kinetic assays, we confirmed that AcH is primarily oxidized by ALDH2 rather than ALDH1A2. We found increases in mRNAs of differentiation-associated genes (Hoxa1, Cyp26a1, and RARb2) upon EtOH treatment of WT and Acss2 À/À ESCs, but not Aldh2 À/À ESCs. The absence of ALDH2 reduced mRNAs of some pluripotency factors (Nanog, Sox2, and Klf4). Treatment of WT ESCs with AcH or 4-hydroxynonenal (4-HNE), another substrate of ALDH2, increased differentiation-associated transcripts compared to levels in untreated cells. mRNAs of genes involved in retinoic acid (RA) synthesis (Stra6 and Rdh10) were also increased by EtOH, AcH, and 4-HNE treatment. Retinoic acid receptor-c (RARc) is required for both EtOH-and AcH-mediated increases in Hoxa1 and Stra6, demonstrating the critical role of RA:RARc signaling in AcH-induced ESC differentiation.Conclusions: ACSS2 knockouts showed no changes in differentiation phenotype, while pluripotency-related transcripts were decreased in ALDH2 knockout ESCs. We demonstrate that AcH increases differentiation-associated mRNAs in ESCs via RARc.

Solutions of ethylenediamine tetraacetic acid and sodium bicarbonate were used to soak faba beans before canning. Soaking in ethylenediamine tetraacetic acid solutions only caused a slightly lighter bean color. Soaking in bicarbonate solutions Increased both the drained weight and the softness of the cooked beans, and it also made the bean color darker. The profiles of loss of both thiamin and riboflavin during the canning process were determined. Riboflavin was lost primarily during retorting while thiamin was lost in several processes including heat pretreatment and soaking. Mechanism of loss for the two vitamins was mainly leaching; very little thermal destruction was observed. None of the soaking treatments affected the retention of these vitamins.

An increasing number of studies have suggested a potential link between sugar consumption and cancer. However, a direct relationship between the two remains controversial. Here, we treated APC -mutant mice daily with a modest amount of high-fructose corn syrup (HFCS) via oral gavage to mimic sugar-sweetened beverage (SSB) consumption and evaluated the effects of SSBs on intestinal tumorigenesis. We observed a dramatic increase in tumor size and tumor grade in HFCS-treated mice despite no signs of obesity or metabolic syndrome. A bolus of HFCS spikes the level of fructose and glucose in the intestinal lumen and serum, respectively, allowing tumors to take up both sugars efficiently. Ketohexokinase (KHK) in tumors rapidly converts fructose to fructose-1-phosphate (F1P), lowering cytosolic ATP in the process. Consequently, this leads to the activation of glycolysis as ATP depletion relieves the allosteric inhibition of phosphofructokinase (PFK), the most critical regulatory enzyme in glycolysis. This accelerated glycolysis contributes to the increased de novo lipogenesis pathway that enhances tumor growth in HFCS-treated mice. Importantly, the deletion of KHK or fatty acid synthase (FASN) in APC -mutant mice abolishes the HFCS-induced metabolic changes and tumor growth. Overall, our results provide a mechanistic rationale for restricting SSB consumption to decrease the rate of growth of early stage colorectal cancers. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.