Low Glucose Kills Cancer Cells while Lengthening the Life of Healthy Cells

canstockphoto10501220During the recent Great Glucose Control teleconference, Anthony, one of our new members, asked an important question: How does glucose affect methylation? I was inspired by his question to find out more.

Methylation is a hot topic right now because it is a biological imprint of the influences of lifestyle and diet on DNA.

We feel lucky to benefit from a brilliant study by Yuanyuan Li and colleagues: It helps us understand that the cellular effects of glucose levels on methylation depend in part on whether you are a normal or a cancer cell. If you are a normal cell, glucose restriction may extend your life in part by decreasing the expression of cellular senescence effector p16. It also activates hTERT (human telomerase reverse transcriptase) a regulator which keeps your telomeres from shortening.

If you are a cancer cell the news is bad: Low glucose does not have the same positive effects on methylation and will likely shorten your life (remember the work of Dr. Tom Seyfried).

Why do these selective beneficial effects happen with glucose restriction?

To quote the researchers “…[G]lucose restriction may induce p16 silencing by influencing DNA methylation processes and, therefore, affect binding of certain key transcription factors such as E2F-1 to the p16 promoter.” This change in turn may contribute to lifespan extension in normal human cells.

However, no methylation changes were found in the hTERT and p16 promoters of immortalized (precancerous) WI-38/S cells, indicating that DNA methylation may not be the main mechanism involved in the induction of gene expression by glucose restriction in precancerous cells.

Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression

Yuanyuan Li, Liang Liu, Trygve O. Tollefsbo

FASEB Journal* 2010 May;24(5):1442-53. doi: 10.1096/fj.09-149328. Epub 2009 Dec 17. *official publication of the Federation of American Societies for Experimental Biology.


Cancer cells metabolize glucose at elevated rates and have a higher sensitivity to glucose reduction. However, the precise molecular mechanisms leading to different responses to glucose restriction between normal and cancer cells are not fully understood. We analyzed normal WI-38 and immortalized WI-38/S fetal lung fibroblasts [which produce collagen, known to be essential to lung structure and function] and found that glucose restriction resulted in growth inhibition and apoptosis in WI-38/S cells, whereas it induced lifespan extension in WI-38 cells. Moreover, in WI-38/S cells glucose restriction decreased expression of hTERT (human telomerase reverse transcriptase) and increased expression of p16INK4a.

Opposite effects were found in the gene expression of hTERT and p16 in WI-38 cells in response to glucose restriction. The altered gene expression was partly due to glucose restriction-induced DNA methylation changes and chromatin remodeling of the hTERT and p16 promoters in normal and immortalized WI-38 cells. Furthermore, glucose restriction resulted in altered hTERT and p16 expression in response to epigenetic regulators in WI-38 rather than WI-38/S cells, suggesting that energy stress-induced differential epigenetic regulation may lead to different cellular fates in normal and precancerous cells. Collectively, these results provide new insights into the epigenetic mechanisms of a nutrient control strategy that may contribute to cancer therapy as well as antiaging approaches.

Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression.

Caloric restriction has been considered a potent physiological approach to cancer prevention and therapy for several decades. The different responses in the consumption and metabolism of glucose, the major caloric source in the human body, between cancer and normal cells could be a promising cancer preventive and/or therapeutic target (1 2 3) . The metabolism of glucose has attracted extensive interest in changes of glycolysis in cancer cells, which is known as the Warburg effect (4) . Alterations in the tumor microenvironment, which is characterized by regions of fluctuating and chronic hypoxia and low extracellular pH contribute significantly to tumor progression (5) . Glucose restriction is a metabolic stressor that triggers several signal transduction pathways (6) . The sensitivity to glucose in many cancer cells has been used successfully for cancer diagnosis and monitoring (7) . Furthermore, glucose restriction results in a cellular stress-induced multiple gene expression alteration response, which includes many cell growth and survival-related genes (8 , 9) . However, the mechanisms by which glucose restriction exerts its effect on carcinogenic processes are only beginning to be elucidated.

Nutrition is believed to be a chief contributor to the regulation of gene expression in both physical and pathological processes by affecting epigenetic pathways, which include two basic processes: DNA methylation and histone modification (10 11 12 13) . Furthermore, caloric restriction-induced prolongation of lifespan in various organisms has been shown to be partly related to the NAD+-dependent histone deacetylase family member, Sirt-1, which is involved in a wide variety of cellular processes, including aging and stress response regulated by epigenetic processes (14). Therefore, epigenetic-mediated changes in gene expression in response to glucose restriction may be a major molecular mechanism linking environmental factors with consequences for cell function in normal and cancer cells.

A key determinant of the enzymatic activity of human telomerase, hTERT (human telomerase reverse transcriptase), has drawn extensive interest recently because its up-regulated expression is present in 90% of malignant tumors but is barely detectable in normal somatic cells (15 , 16) . Another cell cycle regulator gene, p16INK4a, is also believed to play a crucial role in tumor growth suppression and cell senescence (17 , 18) . Notably, both hTERT and p16 are epigenetics-sensitive genes, in that their expression is frequently regulated by epigenetic processes (19 , 20) . Therefore, focusing on the epigenetic modulation of the expression of these two key genes can facilitate elucidation of the influences of epigenetic mechanisms either on normal cells or on cancer cells that have undergone glucose reduction.

To elucidate the role of epigenetic control in normal and cancer cells in response to glucose restriction, we used fetal lung fibroblast WI-38 cells and immortalized WI-38 (WI-38/S) cells, which were derived from WI-38 cells by transfection with simian virus-40 (SV-40) antigen. Analyses of these two types of cells, which exhibit normal and precancerous characteristics, respectively, but share the same origin, provide an opportunity to assess the mechanisms by which the effects of glucose reduction are exerted to influence gene expression through epigenetic regulation.

In the current study, we found that glucose reduction induced growth inhibition and apoptosis in the immortalized cells but not in the normal cells. This result is due, at least in part, to differential modulation of hTERT and p16 expression through DNA methylation changes and/or histone remodeling in normal and immortalized cells in response to glucose restriction. Our findings not only reveal epigenetic mechanisms of caloric restriction on cancer development but also provide new insights into nutrition-related cancer prevention and therapy.


The authors thank Dr. Gordon Peters (Imperial Cancer Research Fund Laboratories, London, UK) and Dr. Silvia Bacchetti (Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada) for kindly providing the luciferase constructs used in this investigation.

  • Received October 30, 2009.
  • Accepted November 19, 2009.



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