Abstract
BackgroundKetogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients. Beta-hydroxybutyrate (3-OHB) is the main physiological ketone body, whose concentration can reach plasma levels of 2–6 mM during KDs or fasting. The impact of 3-OHB on the biology of tumor cells described so far is contradictory. Therefore, we investigated the effect of a physiological concentration of 3 mM 3-OHB on metabolism, proliferation, and viability of breast cancer (BC) cells in vitro.MethodsSeven different human BC cell lines (BT20, BT474, HBL100, MCF-7, MDA-MB 231, MDA-MB 468, and T47D) were cultured in medium with 5 mM glucose in the presence of 3 mM 3-OHB at mild hypoxia (5% oxygen) or normoxia (21% oxygen). Metabolic profiling was performed by quantification of the turnover of glucose, lactate, and 3-OHB and by Seahorse metabolic flux analysis. Expression of key enzymes of ketolysis as well as the main monocarboxylic acid transporter MCT2 and the glucose-transporter GLUT1 was analyzed by RT-qPCR and Western blotting. The effect of 3-OHB on short- and long-term cell proliferation as well as chemo- and radiosensitivity were also analyzed.Results3-OHB significantly changed the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in BT20 cells resulting in a more oxidative energetic phenotype. MCF-7 and MDA-MB 468 cells had increased ECAR only in response to 3-OHB, while the other three cell types remained uninfluenced. All cells expressed MCT2 and GLUT1, thus being able to uptake the metabolites. The consumption of 3-OHB was not strongly linked to mRNA overexpression of key enzymes of ketolysis and did not correlate with lactate production and glucose consumption. Neither 3-OHB nor acetoacetate did interfere with proliferation. Further, 3-OHB incubation did not modify the response of the tested BC cell lines to chemotherapy or radiation.ConclusionsWe found that a physiological level of 3-OHB can change the energetic profile of some BC cell lines. However, 3-OHB failed to influence different biologic processes in these cells, e.g., cell proliferation and the response to common breast cancer chemotherapy and radiotherapy. Thus, we have no evidence that 3-OHB generally influences the biology of breast cancer cells in vitro.
Highlights
Ketogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients
Other cells with a more “glycolytic, Warburg-like phenotype” would be unable to metabolize 3-OHB in which case it could accumulate intracellularly and inhibit tumor growth via signaling and epigenetic mechanisms [50]. In view of this preclinical pro- and contra evidence and the fact that increasing numbers of patients are adopting a ketogenic diet or short-term fasting during oncological therapy, we studied the impact of 3-OHB on seven different breast cancer (BC) cell lines in vitro
In this study, we have shown that beta-hydroxybutyrate (3-OHB), the main ketone body found in the circulation after fasting or ketogenic diets (KDs), was able to change the energetic phenotype of BT20 breast cancer cells when applied at physiological concentrations of 3 mM
Summary
Ketogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients. Modern BC therapy includes different therapeutic approaches, such as surgical removal of the tumor, chemotherapy, radiation, and hormone therapy [2] In addition to these conventional therapies, a large number of patients seek supportive therapies like specific diets to improve their outcome. The correlation between different types of diet and the incidence and progression of cancer is increasingly becoming the focus of research [3,4,5,6,7] In this respect, avoiding carbohydrates to “starve cancer cells” is the most popular trend amongst “cancer diets.”. The rationale for this dietary regime is often based on the “Warburg effect,” which describes the preferential fermentation of glucose to lactate even under availability of sufficient oxygen [8, 9]. Reducing carbohydrate intake and lowering blood glucose seems to be a promising strategy for cutting cancer off from glucose supply [10,11,12]
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