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 ad “glutamine addiction”. This led to the idea that preventing tumors from glutamine uptake could be a potential therapeutic strategy. Researchers from Berlin and Wurzburg, Germany conclude that glutamine deprivation will halt the proliferation of certain tumor cells and has raised the question of whether such therapeutic intervention will lead to remission in cancers. The study is published in The EMBO journal.
Glutamine addiction is often 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 deregulated in cancers. Glutamine deprivation in these systems has shown to be lethal to the cells- does this apply to naturally occurring tumors? Researchers looked at the human colon carcinoma cell lines that innately show high levels of c-MYC. They found that carcinoma cells do not die when they are deprived of glutamine, rather they enter a reversible state of proliferation arrest.
Researchers also 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. Exact role of c-MYC and how it is regulated by glutamine was thus studied.
Key-role 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. Results indicate that c-MYC transcription to nucleotide availability. This coupling does not exist in cell cultures models with exogenously expressed c-MYC – the type of systems that are mainly used to investigate glutamine addiction in cancer. This could lead to errors, newly emerging transcripts will get tangled up, forming loops that are lethal to the cell.
Glutamine addiction has mainly been investigated in cell culture system and may have overestimated lethality of glutamine deprivation, says the researchers.