by Maria Giulia Manzione
To function, human cells require amino acids, which are the basic building blocks of all proteins in our body and are essential for cell survival. Two of these amino acids, serine and glycine, are particularly important because they are needed for the synthesis of DNA, other amino acids, and many important biomolecules such as phospholipids (the molecules that form the cell membrane). In the cell, serine and glycine are made by enzymes, which are proteins that act as catalysts to speed up chemical reactions. Serine is synthesized by the PHGDH enzyme, while glycine is synthesized from serine by the SHMT enzyme. Under stressful conditions, cancer cells need to re-arrange their metabolism involving these amino acids to sustain cell proliferation and tumour growth.
Healthy cells and some tumors mainly take up serine and glycine from external sources such as food. However, some cancers (e.g. certain types of breast cancer and leukemia) are able to synthesize serine and glycine themselves from glucose, the most important simple sugar in human metabolism. These cancers even get addicted to their own intracellular serine/glycine synthesis to sustain their proliferation, creating a vulnerability in these tumors that could be targeted for cancer therapy. Hence, the team of Prof. Bruno Cammue and Dr. Karin Thevissen (Centre for Microbial and Plant Genetics, KU Leuven) used a low-cost and effective model organism, yeast, to screen for available clinically used drugs targeting serine/glycine synthesis (Shauni Lien Geeraerts et al., 2020). This screening revealed the antidepressant sertraline as a novel potential molecule able to inhibit serine/glycine synthesis. Further research by Shauni Geeraerts and Dr. Kim Kampen (Laboratory for Disease Mechanisms in Cancer, KU Leuven) revealed that sertraline inhibits the activity of the enzyme SHMT and that it specifically inhibits the proliferation of breast cancer and leukemia cells that are addicted to their own serine/glycine synthesis (Shauni Lien Geeraerts et al., 2020).
Simplified pathway of serine/glycine synthesis which can be stopped by the inhibition of the SHMT enzyme with the antidepressant drug sertraline. Atoms colour-coded as follows: hydrogen in white, carbon in brown, oxygen in red, nitrogen in blue and chlorine in green.
Since the inhibition of the mitochondria of cells, which produce the chemical energy needed for the cell's biochemical reactions, is known to increase the dependency of cancer cells on serine/glycine synthesis, the researchers tested a combination of sertraline and artemether, an inhibitor of mitochondrial function. The combo-therapy resulted in a stronger anti-cancer effect when compared with the use of sertraline or artemether alone. The results were further confirmed in mice bearing breast cancer.
In addition to certain breast cancers and leukemias, tumors from many other cancer types such as brain tumors, lung cancer and melanoma show an addiction to serine/glycine synthesis. “Additional experiments are needed to test the potential antitumor effects of sertraline in these other tumor types”, according to Prof. Kim De Keersmaecker (Laboratory for Disease Mechanisms in Cancer, KU Leuven).
“Our results are from experimental research, not clinical studies, but we can be optimistic about the potential. The safety of using sertraline in humans has already been well described, which is a great advantage”
In addition, when asked about the benefits of collaborating with different labs on this research Prof. De Keersmaecker stated that “Collaborating with multiple teams brings extra challenges, but it was definitely worth-it. All the contributors have complementary expertises that have all been essential to get to such a nice end-result of our study”.
The study opens a new therapeutic strategy to target cancer types addicted to serine/glycine synthesis. Their findings were essentially driven by two cost-efficient approaches: (1) preliminary screening in yeast —a very useful and easy to manipulate experimental model— and (2) drug repurposing —a strategy for identifying new therapeutic uses for old/approved drugs originally developed for other purposes— which, hopefully, will inspire other researchers in the field.
Addiction to serine/glycine synthesis isn’t the only vulnerability of cancer cells. It will be interesting to test if other antidepressants could be used to disturb other metabolic pathways that sustain tumor growth and to investigate the antitumor effects of sertraline (and/or sertraline plus artemether) in a clinical setting.
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