Disrupting Glutamine Metabolism Slows Liver Cancer Growth

Cancer researchers used a line of genetically engineered mice to demonstrate the dependency of liver cancer cells on the amino acid glutamine as their primary energy source.

Investigators at the Ecole Polytechnique Fédérale de Lausanne (Switzerland) worked with a line of "knock-out" mice that had been genetically engineered to lack the gene for production of the enzyme LRH-1 (liver receptor homolog 1). LRH-1 is a member of the nuclear receptor family of intracellular transcription factors and plays a critical role in the regulation of development, cholesterol transport, bile acid homeostasis, and steroidogenesis.


The investigators reported in the June 1, 2016, issue of the journal Genes & Development that gain and loss of function of LRH-1 in the liver modulated the expression and activity of mitochondrial glutaminase 2 (GLS2), the first and rate-limiting step of the glutamine pathway.

Closing down this pathway by eliminating LRH-1 prevented the utilization of glutamine as a fuel and put the cancerous cells into tremendous metabolic distress. Acute and chronic deletion of LRH-1 in the liver prevented the deamination of glutamine and reduced glutamine-dependent anaplerosis (the process of replenishment of depleted metabolic cycle or pathway intermediates).

The reduction in the lysis of glutamine limited the availability of alpha-ketoglutarate, which in turn inhibited mTORC1 (mammalian target of rapamycin (mTOR) complex 1) signaling to eventually block cell growth and proliferation.

"Inhibiting LRH-1 can thus be an effective way to starve only liver cancer cells, while leaving normal cells intact," said contributing author Dr. Kristina Schoonjans, head of the laboratory of metabolic signaling at the Ecole Polytechnique Fédérale de Lausanne.

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