Credit: Armin Kübelbeck
Preclinical experiments may have revealed why some cancer patients do not respond to retinoic acid.
Investigators found that a protein known as AEG-1 blocks the effects of retinoic acid in acute myeloid leukemia (AML) and liver cancer.
They also noted that AEG-1 is overexpressed in nearly every cancer type, so these findings could impact the care of countless cancer patients.
The team reported their findings in Cancer Research.
The group’s experiments revealed that AEG-1 binds to retinoid X receptors (RXR), which help regulate cell growth and development. RXR is typically activated by retinoic acid, but the overexpressed AEG-1 proteins found in cancer cells block these signals and help promote tumor growth.
“Our findings are the first to show that AEG-1 interacts with the retinoid X receptor,” said study author Devanand Sarkar, MBBS, PhD, of Virginia Commonwealth University Massey Cancer Center in Richmond.
Specifically, he and his colleagues found that AEG-1 protected hepatocellular carcinoma cells and AML cells from retinoid- and rexinoid-induced cell death.
But in nude mouse models, blocking the production of AEG-1 allowed all-trans retinoic acid to kill hepatocellular carcinoma cells.
The investigators therefore believe that targeting AEG-1 could sensitize AML patients and those with hepatocellular carcinoma to retinoid- and rexinoid-based therapies.
“This research has immediate clinical relevance, such that physicians could begin screening cancer patients for AEG-1 expression levels in order to determine whether retinoic acid should be prescribed,” Dr Sarkar added.
He and his colleagues have been studying AEG-1 for years. They were the first to create a mouse model demonstrating the role of AEG-1 in liver cancer, and they have been working to develop targeted therapies that block AEG-1 production.
The present study expanded their knowledge of the molecular interactions of AEG-1.
“We are continuing to test combination therapies involving AEG-1 inhibition and retinoic acid in animal models, and the initial results are promising,” Dr Sarkar said. “If we continue to see these results in more complex experiments, we hope to eventually propose a phase 1 clinical trial in patients with liver cancer.”
