Serine and Glycine (The stealth cancer promoters)

Chances are that if you were to look through your supplements in your cupboard you may find some forms of serine and glycine contained among the ingredients. These amino acids are increasingly pervasive in a large number of nutritional supplements currently flooding the market. Serine and glycine are two biosynthetically linked molecules that together provide essential precursors for the synthesis of proteins, nucleic acids and lipids that are crucial for cell growth. There are often conjugated with other essential minerals such as magnesium, zinc and iron in order to increase bioavailability. They are often found in supplements for cognitive enhancement, liver detoxification, muscle tension, methylation disorders, deficiencies and other conditions.

The Two Faces of Serine/Glycine

The positive benefits of serine/glycine are that they affect genetic transcription via biosynthetic pathways which also affect sugar metabolism in the liver known as glycolysis. Synthesis or conversion of serine to glycine is integrated by serine hydroxymethyltransferase (SHMT). Glycine is a major source of methyl groups for the one-carbon pools needed for the biosynthesis of glutathione (GSH). Glycine is also used for the biosynthesis of purines (often associated with gout), protein and DNA/histone methylation. While these pathways are considered to have positive outcomes from serine/glycine there just might be an unfortunate result lurking below the surface. It is clear that there are many benefits from the actions of these molecules however there is emerging evidence of a “dark side” that remains mostly unreported. When manufacturers are confronted with the potential carcinogenesis linked with serine/glycine their rebuttals usually include safe dose related statements and articles supporting their efficacy. There seems to be no clear guideline as to what is considered a safe dosage for patients including those with cancer and cancer survivors. This article will review some of the technical evidence and help shed light on whether potential hazards relating to cancer promotion really exist.

Research Studies

Early and recent investigations have focused on the role of gastrin in cancer of the digestive system. For decades it has been known that glycine enhances the trophic expression of gastrin. One study examined the effects of “glycine extended gastrin” (Gly-G) on rat pancreatic and human gastric (AGS) cancer cells. Results showed that glycine stimulated growth of human gastric cancer cells through gastrin/cholecystokinin (CCK)-beta receptors (Iwase et al. 1997). Similar results were supported by an investigation examining glycine induced gastrin’s effect on human colon (LoVo, HT29, HCT 116, Colo 320DM and T84) cancer cell lines. The study explored the possibility that glycine may have an effect on gastrin as human colon cancer contains progastrin-processing intermediates. The results of the study showed that glycine extended gastrin’s trophic emerging effects via an MEK-independent mechanism and stimulated jun-kinase activity in human colon LoVo and HT-29 cancer cells. This study confirmed glycine’s role in promotion of human colon cancer cell growth (Stepan et al. 1999). Recently, gastrin has been shown to play a role in stimulation of growth of several gastrointestinal cancers. Gastrin expression is also found in many gastric adenocarcinomas of the stomach corpus. Gastrin’s actions are mediated through the G-protein-coupled receptor cholecystokinin-B (CCK-B) on parietal and entrochromaffin cells of the gastric body and stem cells (Smith et al. 2017).

It is interesting to note that glycine can also be generated from threonine via the enzymes; threonine dehydrogenase (TDH) and glycine C-acetyltranferase (GCAT). In vitro threonine deprivation has been shown to promote cell death that is associated with a reduction in histone methylation. Metabolic flux demonstrates that threonine enters one-carbon metabolism through glycine cleavage (Shyh-Chang et al. 2013).

Promotion of Cancer via Gene Pathways

Serine/glycine while being central for metabolism of biosynthetic reactions can have an unfortunate effect of promoting cancer proliferation by various mechanisms. This is demonstrated by serine/glycine’s ability to upregulate phoshoglycerate dehydrogenase (PHGDH) which is a carcinogenesis promoter (Possemato et al. 2011).

In normal metabolism the suppression of PHGDH inhibits the proliferation of cancer growth. Serine unfortunately fuels intermediates that sustain cancer metabolism. The serine synthesis pathway utilises the glycolytic intermediate 3P-glycerate, which is converted by PHGDH, PSAT-1 and PSPH into serine. PSAT-1 uses the PHGDH product 3-phosphohydroxypyruvate to convert glutamate to alpha-ketoglutarate. Alpha-ketoglutarate is an anaplerotic intermediate that refuels the TCA cycle that sustains cancer cell metabolism. This has implications on tumor suppressor p53 in its role in cancer cell homeostasis. P53 has been associated with the capacity of cancer cells to deal with serine starvation and oxidative stress. Cells lacking p53 fail to respond to serine starvation due to oxidative stress which leads to reduced viability and severely impaired proliferation. During serine starvation activation of p-53-p21 axis leads to cell cycle arrest, which promotes cell survival by efficiently channelling depleted serine stores to glutathione synthesis (Maddocks et al. 2013).

Various Pathways and Mechanisms for Cancer Proliferation

The Warburg effect adopts the premise that cancer cells reprogram their metabolism to counteract reactive oxygen species (ROS) via aerobic glycolysis. Serine/glycine not only has a significant role in the glycolytic metabolism of cancer cells, other findings suggest that the p53-family member p73 also plays a role in serine biosynthesis. Metabolic profiling of human cancer cells reveals that Tap73 activates serine biosynthesis resulting in increased intracellular levels of serine, glycine and GSH. Tap73 depletion abrogates cancer cell proliferation during serine/glycine deprivation supporting the role of p73 in helping cancer cells under metabolic stress. These recent findings support the importance of p73 and p53 in helping cancer cells during oxidative stress associated with serine depletion. In light of their importance for antioxidant response, it is interesting to consider the investigation of serine/glycine biosynthesis in the early stage of tumorigenesis (Amelio et al. 2013).

More Epigenetic Implications

While many cancer cells show sensitivity to serine depletion other cancer cells can circumvent serine dependence through genetic alterations such as the before mentioned PHGDH upregulation which increases serine biosynthesis. The approach of targeting mechanisms downstream of serine/glycine/one-carbon metabolism has the focus on modulating epigenetic status of tumor inhibitors of methytransferases which affect post-translational modifications of histones and DNA belonging to this group (Stresemann et al. 2006).

One carbon metabolism involving the folate and methionine cycle integrates carbon units from amino acids, including serine and glycine. This process can generate multiple outputs such as biosynthesis of lipids, nucleotides and proteins, redox status and substraites for methylation reactions. Hyperactivation of this pathway has been investigated as a possible driver of oncogenesis linked to epigenetic status (Locasale et al. 2013).

A Chemotherapy Platform?

An early inquiry into the oncogenic potential of serine found that human cytosolic serine hydroxymethyltransferase (SHMT) has a crystal structure. SHMT has demonstrated that it could serve as a targeting enzyme platform when combined with chemotherapy (Renwick et al. 1998). This has lead to identification of novel strategies such as antifolate metabolism drugs such as 5-fluorouricil (5-FU), Methotrexate and Pemetrexed which constitute a group of chemotherapies for a wide range of cancers. These include acute lymphoblastic leukemia, lymphomas, breast and bladder cancer. These drugs have an ability to bind to SHMT in vitro as well as inhibit thymidylate synthesis and purine biosynthesis. Taking advantage of serine’s affinity with cancer mechanisms has resulted in a novel approach to deliver the chemotherapy to the cancer (Daidone et al. 2011).

Recent studies have supported that cancer has a preference for serine over glycine within the one-carbon metabolism and that glycine cannot substitute for serine to support nucleotide synthesis (Labuschagne et al. 2014).

Caution should be considered

Although one study demonstrates cancer’s preference for serine over glycine, excess glycine can still be converted to serine. From the evidence discussed in this article there are still many intricacies concerning glycine/serine biosynthesis yet to be elucidated. It has been known from oncology investigations that the average person produces at least 5,000 cancer cells per day. In a normal healthy individual these cancer cells are routinely neutralized by the immune system. It has also been shown that there are ever increasing types of DNA mutations and immune compromising maladies that the average person is exposed to. The author’s perspective on this subject is that; professional practitioners should exercise caution in prescribing supplements containing these ingredients in whatever form, especially to cancer patients or cancer survivors.

References:

Iwase K, Evers BM, Hellmich MR, Guo TS, Hicashide S, Kim HJ, Townsend CM Jr. Regulation of Growth of Human Gastric Cancer by Gastrin and Glycine-extended Progastrin. Gastroenterology Vol113 (3) Sept 1997: 782-790 (PubMed).
Stepan VM, Sawada M, Todisco A, Dickenson CJ. Glycine-Extended Gastrin Exerts Growth-Promoting Effects on Human Colon Cancer Cells. Mole Med. 5:147-159, 1999 (PubMed).
Shyh-Chang N. Et al. 2013 Influence of Threonine Metabolism on s-adenosylmethionine and histone Methlyation. Science 339, 222-226.
Smith JP, Nadella S, Osborne N. Gastrin and Gastric Cancer. Cell Mole Gastroenterol Hepatol. 2017 July; 4 (1): 75-83 (PubMed).
Possemato R. Functional Genomics reveal that the Serine Synthesis Pathway is Essential in Breast Cancer. Nature 2011; 476: 346-350 (PubMed).
Maddocks OD. Serine Starvation Induces Stress and p53-dependent Metabolic Remodelling in Cancer Cells. Nature 2013: 493: 542-546 (PubMed).
Amelio I. P73 regulates serine biosynthesis in cancer. Oncogene 2013 (PubMed).
Stresemann C. Functional diversity of DNA methyltranferase inhibitors in human cancer cell lines. Cancer Res. 2006; 66: 2794-2800 (PubMed).
Locasale JW. Serine, glycine and the one-carbon cycle: Cancer Metabolism in Full Circle. Nat Rev Cancer 2013 Aug; 13 (8): 572-583 (PubMed).
Renwick SB. The Crystal Structures of Human Cytosolic Serine Hydroxymethyltranferase: A target for Cancer Therapy. Structure. 1998: 1105-1116 (PubMed).
Daidone F. In silico and in vitro validation of serine hydroxymethyltransferase as a chemotherapeutic target of antifolate drug Pemetrexed. Eur J Med Chem 2011; 46: 1616-1621 (PubMed).
Labuschagne C, van den Broek NJF, MacKay GM, Vousden KH, Maddocks ODK. Serine but not Glycine, supports One-Carbon Metabolism and Proliferation of Cancer Cells https://doi.org/10.1016/j.celrep.2014.04.045