Starving Liver Cancer Cells By Blocking Their Metabolism

A method to starve liver cancer cells has been uncovered by scientists at Ecole Polytechnique Federale de Lausanne. Blocking a protein that is required for glutamine breakdown cuts off their food supply, while leaving normal cells intact. The discovery opens new ways to treat liver cancer.

Primary liver cancer is the second leading cause of cancer-related deaths worldwide, with current treatments being very limited. Liver cancer cells are particularly addicted to the amino acid glutamine, which fuels their proliferation.

EPFL scientists have now found that a liver protein called liver receptor homolog 1 (LRH-1) is responsible for the digestion of glutamine into smaller molecules, which are avidly consumed by liver cancer cells. Therefore, blocking LRH-1 causes cancer cells to starve and greatly reduces the development of liver cancer in mice, while preserving normal cells.

The discovery could lead to new drugs that target LRH-1 to effectively treat liver cancers.

Liver Receptor Homolog 1

LRH-1 is a receptor in the cell nucleus, where it regulates the expression of various genes. In this study, scientists from different groups at EPFL led by Kristina Schoonjans, discovered that LRH-1 coordinates several key genes that are involved in the metabolism of glutamine—an amino acid to which liver cancer cells become addicted.

The researchers found that LRH-1 drives the development of liver tumors by helping cancer cells to convert glutamine into molecules that are directly needed for proliferation.

This would also mean that disrupting the function of LRH-1 in the liver of mice would protect against the development of liver cancer. That is exactly what the scientists found when they studied mice that had been genetically modified to not express LRH-1, so called “knockout” mice.

After exposing them to chemical carcinogens, the livers of knockout mice showed dramatically less development of tumors.

“Shutting down this pathway by inhibiting LRH-1 abrogates the utilization of glutamine as a fuel and brings the cancerous cells in tremendous metabolic distress,” says first author Pan Xu.

Based on the study, LRH-1 could be a new drug target to prevent the development of liver cancer. Because cancer cells, unlike normal cells, are very often addicted to glutamine, drugs that inhibit glutamine metabolism have been proposed as new highly efficient chemotherapy agents.

The study was supported by École Polytechnique Fédérale de Lausanne funding, the Swiss Cancer League, and the Swiss National Science Foundation. Co-author Sokrates Stein is supported by a post-doctoral fellowship from the Novartis Consumer Health Foundation, and co-author Johan Auwer is the Nestle Chair in Energy Metabolism.

Pan Xu et al
LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer
Genes & Development (2016). DOI: 10.1101/gad.277483.116

Image: Fluorescent image of liver cells. Credit: Kristina Schoonjans/EPFL