Novel approach combines glutaminase and HuR blockade to suppress breast cancer growth

Glutaminase inhibition is therefore a common target for cancer treatment, but the researchers innovated by focusing on how HuR regulates the RNA metabolism of glutaminase as a strategy to enhance its efficacy.

High levels of HuR correlate with increased expression of genes linked to cancer cell proliferation and survival, suggesting poor patient prognosis. Regulation of this protein may therefore also be a promising therapeutic target. "Inhibitors of small HuR molecules have been identified, and novel formulations for targeted delivery to tumor cells have been developed with promising anti-cancer activity," Dias said.

Isoforms

The findings show that HuR, which is often overexpressed in cancer patients, plays a vital role in ensuring that the right isoform of glutaminase is produced. "When levels of HuR are low, production of GAC increases to convert glutamine to glutamate more quickly," Adamoski said.

To reduce the expression of HuR, the researchers reduced the isoform KGA and increased GAC, making the metabolism of the cancer cells even more dependent on glutamine than usual. "By reducing HuR and at the same time inhibiting glutaminase chemically, we were able to bring about a significant drop in breast cancer cell growth and invasion," he said.

The other co-authors of the study are researchers affiliated with CNPEM and State University of Campinas (UNICAMP) in Brazil, Washington University School of Medicine and University of Texas in the U.S., and Iuliu-Hatieganu University of Medicine in Romania.

This previous study elucidated the mechanisms whereby glutaminase activity intensifies via the formation of filaments in mitochondria. The discovery is important because tumor metabolism dysregulation plays a key role in cancer and metastasis, and is associated with poor breast cancer patient prognosis.

Source:Journal reference:

https://www.nature.com/articles/s41467-024-49874-x