It was recently discovered that
glycine consumption is strongly related to the rate of proliferation across
cancer cells. This is very intriguing and raises the question of what is the actual role of this
amino acid in
cancer metabolism.
Cancer cells are greedy for
glycine. In particular, the mitochondrial production of
glycine seems to be utterly important. Overexpression of mitochondrial
serine hydroxymethyltransferase, the
enzyme converting
l-serine to
glycine, assures an adequate supply of
glycine to rapidly proliferating
cancer cells. In fact, silencing of mitochondrial
serine hydroxymethyltransferase was shown to halt
cancer cell proliferation. Direct incorporation of
glycine carbon atoms into the
purine ring has been proposed to be one main reason for the importance of
glycine in
cancer cell metabolism. We believe that, as far as the importance of
glycine in
cancer is concerned, a central role of this
amino acid, namely its participation to
heme biosynthesis, has been neglected. In mitochondria,
glycine condenses with
succinyl-CoA to form
5-aminolevulinate, the universal precursor of the different forms of
heme contained in
cytochromes and oxidative phosphorylation complexes. Our hypothesis is that mitochondrial
serine hydroxymethyltransferase is fundamental to sustain
cancer metabolism since production of
glycine fuels
heme biosynthesis and therefore oxidative phosphorylation. Respiration of
cancer cells may then ultimately rely on endogenous
glycine synthesis by mitochondrial
serine hydroxymethyltransferase. The link between mitochondrial
serine hydroxymethyltransferase activity and
heme biosynthesis represents an important and still unexplored aspect of the whole picture of
cancer cell metabolism. Our hypothesis might be tested using a combination of metabolic tracing and gene silencing on different
cancer cell lines. The experiments should be devised so as to assess the importance of mitochondrial
serine hydroxymethyltransferase and the
glycine deriving from its reaction as a precursor of
heme. If the observed increase of
glycine consumption in rapidly proliferating
cancer cells has its basis in the need for
heme biosynthesis, then mitochondrial
serine hydroxymethyltransferase should be considered as a key target for the development of new chemotherapeutic agents.