In vitro quantification: Long-term effect of glucose deprivation on various cancer cell lines

Mathews, E.H.; Visagie, Michelle Helen; Meyer, Albertus A.; Joubert, Anna Margaretha; Mathews, George E.

doi:10.1016/j.nut.2020.110748

Cited by 10 publications

(9 citation statements)

References 33 publications

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“…Reduction in glucose availability decreased proliferation in breast cancer cells. Similarly, glucose restrictions affected breast cancer cells in vitro in long term glucose deprivation experiments (40). We did not observe any changes in cell proliferation when breast cancer cells were treated with BHB in low glucose conditions (Fig.…”

Section: Discussionmentioning

confidence: 54%

β‑hydroxybutyrate does not alter the effects of glucose deprivation on breast cancer cells

et al. 2020

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Ketogenic diets have the potential to lower glucose availability to cancer cells. However, the effect that the resulting increase in ketone bodies has on cancer cells is not fully understood. The present study explored the effect of β-hydroxybutyrate (BHB) on glucose-deprived MCF-7 and T47D breast cancer cells. Cell proliferation was decreased in response to lower glucose conditions, which could not be rescued consistently by 10 or 25 mM BHB supplementation. In addition, gene expression levels were altered when cells were glucose deprived. Reducing glucose availability of cancer cells to 225 mg/l for 4 days significantly decreased the expression of 113 genes and increased the expression of 100 genes in MCF-7 breast cancer cells, and significantly decreased the expression of 425 genes and increased the expression of 447 genes in T47D breast cancer cells. Pathway enrichment analysis demonstrated that glucose deprivation decreased activity of the Hippo-Yap cell signaling pathway in MCF-7 breast cancer cells, whereas it increased the expression of genes in the NRF2-pathaway and genes regulating ferroptosis in T47D breast cancer cells. Treatment of glucose-deprived cells with 10 or 25 mM BHB significantly changed the expression of 14 genes in MCF-7 breast cancer cells and 40 genes in T47D breast cancer cells. No significant pathway enrichment was detected when glucose-deprived cells were treated with BHB. Both cell lines expressed the enzymes (OXCT1/2, BDH1 and ACAT1/2) responsible for metabolizing BHB to acetyl-CoA, yet expression of these enzymes was not altered by either glucose deprivation or BHB treatment. In the publicly available The Cancer Genome Atlas (TCGA), increased expression of ketone body-catabolizing enzymes was observed in various types of cancer based on mRNA expression z-scores. Increased expression of BDH1 and ACAT1 significantly decreased overall survival of patients with breast cancer in TCGA studies, while decreased OXCT1 expression non-significantly decreased overall survival. In conclusion, neither MCF-7 nor T47D breast cancer cells were affected by BHB during glucose deprivation; however, screening of tumors for activation of ketone body-metabolizing enzymes may be able to identify patients that will benefit from ketogenic diet interventions.

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Section: Discussionmentioning

confidence: 54%

β‑hydroxybutyrate does not alter the effects of glucose deprivation on breast cancer cells

et al. 2020

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“…Indirect evidence suggests that estrogen may act as an essential or hemi-essential resource in line with Liebig's Law. Mathews et al (2020) quantified the effect of long-term glucose deprivation on various cancer cell lines in vitro. Cell lines were stabilized at typical human glucose level of 6 mmol/L, with the intervention group then receiving 3 mmol/L of glucose for 90 days.…”

Section: Discussionmentioning

confidence: 99%

Estrogen as an Essential Resource and the Coexistence of ER+ and ER– Cancer Cells

Kareva

Brown

2021

Front. Ecol. Evol.

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Diagnosis of estrogen sensitivity in breast cancer is largely predicated on the ratio of ER+ and ER– cancer cells obtained from biopsies. Estrogen is a growth factor necessary for cell survival and division. It can also be thought of as an essential resource that can act in association with other nutrients, glucose, glutamine, fatty acids, amino acids, etc. All of these nutrients, collectively or individually, may limit the growth of the cancer cells (Liebig’s Law of the Minimum). Here we model estrogen susceptibility in breast cancer as a consumer-resource interaction: ER+ cells require both estrogen and glucose as essential resources, whereas ER– only require the general resource. The model predicts that when estrogen is the limiting factor, other nutrients may go unconsumed and available at higher levels, thus permitting the invasion of ER– cells. Conversely, when ER– cells are less efficient on glucose than ER+ cells, then ER– cells limited by glucose may be susceptible to invasion by ER+ cells, provided that sufficient levels of estrogen are available. ER+ cells will outcompete ER– cells when estrogen is abundant, resulting in low concentrations of interstitial glucose within the tumor. In the absence of estrogen, ER– cells will outcompete ER+ cells, leaving a higher concentration of interstitial glucose. At intermediate delivery rates of estrogen and glucose, ER+ and ER– cells are predicted to coexist. In modeling the dynamics of cells in the same tumor with different resource requirements, we can apply concepts and terms familiar to many ecologists. These include: resource supply points, R∗, ZNGI (zero net growth isoclines), resource depletion, and resource uptake rates. Based on the circumstances favoring ER+ vs. ER– breast cancer, we use the model to explore the consequences of therapeutic regimens that may include hormonal therapies, possible roles of diet in changing cancer cell composition, and potential for evolutionarily informed therapies. More generally, the model invites the viewpoint that cancer’s eco-evolutionary dynamics are a consumer-resource interaction, and that other growth factors such as EGFR or androgens may be best viewed as essential resources within these dynamics.

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“…Besides well-known prognostic factors such as age, stage of disease, HER2-Neu expression, and estrogen and progesterone receptor status, factors relating to the cancer patient's metabolism such as obesity [3,4], sarcopenia [5,6], insulin levels [7,8], and chronic hyperglycemia [9][10][11] have been shown to possess a prognostic role. Evidence for a causal influence of these metabolic factors comes from preclinical data showing that breast cancer cells are stimulated by insulin [12] and certain adipokines [13] and are vulnerable to glucose restriction [14,15]. Unfortunately, a large proportion of newly diagnosed breast cancer patients exhibit high fasting blood glucose levels [16], obesity, and low muscle mass [5,6].…”

Section: Introductionmentioning

confidence: 99%

Impact of a ketogenic diet intervention during radiotherapy on body composition: III—final results of the KETOCOMP study for breast cancer patients

et al. 2020

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Background: Obesity and low muscle mass are associated with worse outcomes of breast cancer patients. We conducted a controlled trial to study the impact of a ketogenic diet (KD) based on natural foods versus an unspecified standard diet (SD) on body composition in breast cancer patients undergoing radiotherapy. Methods: Patients with non-metastasized breast cancer were allocated to either the KD (N = 32) or the SD (N = 31) during radiotherapy. Body composition was measured weekly by bioimpedance analysis. Blood parameters and quality of life were assessed before, during, and at the end of radiotherapy. Results: A total of 29 KD and 30 SD patients completed the study. During radiotherapy, mean and median fasting BHB concentrations in the KD group were 0.72 and 0.49 mmol/l (range 0.06-4.9) which was significantly higher than those in the SD group (p < 2.2 × 10 −16). There was a very small and insignificant increase in body weight and fat mass in the SD group, as well as a decrease of fat free mass. In contrast, patients in the KD group lost body weight and fat free and skeletal muscle mass quickly after diet onset, which for the most part was related to water losses. The KD did not cause further substantial changes in fat free or skeletal muscle mass, but was associated with a gradual decrease of 0.4 kg body weight and fat mass per week (p < 0.0001). The KD significantly decreased free T3 levels by 0.06 pg/ml/week (p = 6.3 × 10 −5). Global quality of life remained stable in the SD group but increased in the KD group from a score of 66.7 to 75.0 (p = 0.20). Conclusions: In breast cancer patients undergoing curative radiotherapy, a KD based on natural foods is feasible. After initial water losses, the KD tends to reduce body weight and fat mass while preserving fat free and skeletal muscle mass. Trial registration: ClinicalTrials.gov identifier: NCT02516501, registered on August 06, 2015.

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In vitro quantification: Long-term effect of glucose deprivation on various cancer cell lines

Cited by 10 publications

References 33 publications

β‑hydroxybutyrate does not alter the effects of glucose deprivation on breast cancer cells

β‑hydroxybutyrate does not alter the effects of glucose deprivation on breast cancer cells

Estrogen as an Essential Resource and the Coexistence of ER+ and ER– Cancer Cells

Impact of a ketogenic diet intervention during radiotherapy on body composition: III—final results of the KETOCOMP study for breast cancer patients

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