EMBO: Most cancers require large amounts of glutamine for rapid growth and there are numerous studies indicating that they cannot survive without it, a phenomenon termed “glutamine addiction”. This has fueled the idea that preventing tumors from glutamine uptake could be a potential therapeutic strategy. A study by researchers from Berlin and Würzburg, Germany, now concludes that while glutamine deprivation will halt the proliferation of certain tumor cells, most of them will not be killed, raising questions of whether such a therapeutic intervention will lead to remission in cancers. The study is published today in The EMBO Journal.
Glutamine addiction has often been studied in cell culture systems
that are genetically altered to overproduce c-MYC, a central regulator
of growth and proliferation in all cells that is frequently de-regulated
in cancers. Glutamine deprivation in these systems has been shown to be
lethal to the cells – but does this also apply to naturally occurring
tumors? To address this question, the research teams from Berlin and
Würzburg took a closer look at human colon carcinoma cell lines that
innately show high levels of c-MYC. They found that these carcinoma
cells do not die when glutamine is deprived, but rather enter a
reversible state of proliferation arrest.
Moreover, the researchers discovered that cell culture systems that
express excess c-MYC and naturally occurring colon carcinoma cells
differ in the way c-MYC production is regulated. In the cell culture
systems, c-MYC protein will always be at a high level. In contrast,
c-MYC-levels in colon carcinoma cells are down-regulated upon glutamine
deprivation. This suggested that c-MYC may be involved in killing the
cells upon glutamine deprivation. The researchers thus investigated the
exact role of c-MYC and how it is regulated by glutamine.
Glutamine is used in many cellular pathways, including for the making
of nucleotides, the building blocks of DNA and RNA. When glutamine is
low, the level of nucleotides will drop. The researchers found that
this, in turn, causes c-MYC levels to fall as well.
A key function of c-MYC is to regulate the transcription of numerous
genes. Thus, when nucleotide levels are low and c-MYC concentration
drops, transcription will be down-regulated as well. “Our results
indicate that c-MYC couples transcription to nucleotide availability,”
said Stefan Kempa of the Max-Delbrück-Center for Molecular Medicine in
Berlin, one of the lead investigators of the study. “It makes perfect
sense for the cell to have such a mechanism and not even try to produce
RNA when its building blocks are lacking.”
However, this coupling does not exist in cell culture models with
exogenously expressed c-MYC – the type of systems that are mainly used
to investigate glutamine addiction in cancer. In these cells, the
transcription machinery will keep running upon glutamine deprivation,
despite the fact that there are too few nucleotides. This can lead to
errors; newly emerging transcripts will get tangled up, forming loops
that are lethal to the cell. “The fact that glutamine addiction has
mainly been investigated in cell culture systems may have overestimated
the lethality of glutamine deprivation,” said Martin Eilers, University
of Würzburg, who led the study together with Kempa.
The 3’-UTR of MYC couples RNA polymerase II function to ribonucleotide levels
Francesca R. Dejure, Nadine Royla, Steffi Herold, Jacqueline Kalb,
Susanne Walz, Carsten P. Ade, Guido Mastrobuoni, Jens Vanselow, Andreas
Schlosser, Elmar Wolf, Stefan Kempa and Martin Eilers.
Read the paper: DOI 10.15252/embj.201796662