Protecting against Liver Cancer by Removing the Feed Trough

    Scientists at Ecole Polytechnique Federale De Lausanne (EPFL) say they have found a way to starve liver cancer cells by blocking a protein that is required for glutamine breakdown, 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 discovered that a liver protein called liver receptor homolog 1 (LRH-1) is responsible for the digestion of glutamine into smaller molecules, which are then 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 (“LRH-1-Dependent Programming of Mitochondrial Glutamine Processing Drives Liver Cancer”) is published in Genes & Development and can introduce new drugs that target LRH-1 to treat liver cancers effectively.

    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, Ph.D., discovered that LRH-1 coordinates several key genes that are involved in the metabolism of glutamine. 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 Pan Xu, Ph.D., the first author of the study.

    LRH-1 could be a new drug target to prevent the development of liver cancer.

    “Inhibiting LRH-1 can thus be an effective way to starve only liver cancer cells, while leaving normal cells intact,” says Dr. Schoonjans. Her lab is now actively trying to identify new chemotherapeutic agents to treat liver cancer by developing specific compounds that inhibit LRH-1. The researchers also hope that these findings may extend to other types of cancer, as LRH-1 is also abundant in the pancreas and ovaries.