Fructose contributes to the Warburg effect for cancer growth

Abstract

Obesity and metabolic syndrome are strongly associated with cancer, and these disorders may share a common mechanism. Recently, fructose has emerged as a driving force to develop obesity and metabolic syndrome. Thus, we assume that fructose may be the mechanism to explain why obesity and metabolic syndrome are linked with cancer. Clinical and experimental evidence showed that fructose intake was associated with cancer growth and that fructose transporters are upregulated in various malignant tumors. Interestingly, fructose metabolism can be driven under low oxygen conditions, accelerates glucose utilization, and exhibits distinct effects as compared to glucose, including production of uric acid and lactate as major byproducts. Fructose promotes the Warburg effect to preferentially downregulate mitochondrial respiration and increases aerobic glycolysis that may aid metastases that initially have low oxygen supply. In the process, uric acid may facilitate carcinogenesis by inhibiting the TCA cycle, stimulating cell proliferation by mitochondrial ROS, and blocking fatty acid oxidation. Lactate may also contribute to cancer growth by suppressing fat oxidation and inducing oncogene expression. The ability of fructose metabolism to directly stimulate the glycolytic pathway may have been protective for animals living with limited access to oxygen, but may be deleterious toward stimulating cancer growth and metastasis for humans in modern society. Blocking fructose metabolism may be a novel approach for the prevention and treatment of cancer.

Cerebral Fructose Metabolism as a Potential Mechanism Driving Alzheimer’s Disease

“…risk for hypertension (Jalal et al, 2010), systemic inflammation (Cox et al, 2011), and cancer metastases and growth (Goncalves et al, 2019;Nakagawa et al, 2020).…”

“…Lactate generation occurs that enhances mitochondrial dysfunction (San-Millán and Brooks, 2017 ). As a consequence, total energy production stays low, with much of the energy being produced by aerobic glycolysis (Warburg effect; Nakagawa et al, 2020 ). This helps cells maintain the low energy state in concert with the fall in intracellular ATP levels.…”

“…While dietary fructose is a major source of fructose, endogenous production of fructose may also drive the metabolic syndrome, such as in response to high glycemic carbohydrates and high salt diets (Lanaspa et al, 2013 , 2018 ). There is also evidence that excessive fructose increases the risk for hypertension (Jalal et al, 2010 ), systemic inflammation (Cox et al, 2011 ), and cancer metastases and growth (Goncalves et al, 2019 ; Nakagawa et al, 2020 ).…”

Fructose Metabolism in Cancer

“…Although we will focus on the link between fructose metabolism and cancer, we will briefly mention other diseases affected by fructose metabolism, as some of them are known risk factors for cancer development. For more details, we refer to other reviews [7,[17][18][19]. To date, there are three known inborn errors in fructose metabolism: essential or benign fructosuria due to KHK deficiency; hereditary fructose intolerance and fructose-1,6-bisphosphatase (FBPase) deficiency [19].…”

“…In the following, we will describe the metabolic fates of fructose in humans and the key enzymes involved in fructose metabolism. Furthermore, we give a short overview of known correlations between fructose consumption and non-cancer diseases like obesity, diabetes, and metabolic syndrome, as they are major risk factors for the development of many different cancer types [5,6], also reviewed in [7]. Subsequently, we will highlight the link between fructose metabolism and cancer cell proliferation, focusing on how fructose is metabolized in different types of cancer, which enzymes are involved, and how fructose metabolism is associated with cancer development and outcome.…”