Research led by Brazilians and published in the magazine Nature Communications proposes a combined strategy to combat breast cancer which targets two proteins essential for tumor progression: HuR and the enzyme glutaminase.
The metabolic needs of tumor cells are associated with a large consumption of glutamine for energy production, and the first step is its conversion into glutamate. This is done by the action of the enzyme glutaminase, which has three isoforms (GAC, KGA and LGA) that relate differently to tumor progression. For this reason, the researchers point out, it is a good target for treatments.
“Glutaminase is important because it transforms glutamine into compounds that feed the cells’ energy cycle and production of inputs – essential, therefore, for cancer cells, which have a very active metabolism to sustain their rapid growth,” explains researcher Douglas Adamoski, first author of the article and a FAPESP doctoral fellow.
Acting on glutaminase, therefore, reducing its action, is an important focus of treatments. However, the group of researchers combined another strategy and further improved the results. The work innovates by focusing on how the metabolism of glutaminase RNA is regulated by the HuR protein.
“Another important point of the work is that it explores, in an unprecedented way, the role of HuR in the broader control of cellular metabolism. In the work, we show how this protein regulates the metabolism of tumor cells, affecting important metabolic genes. This includes pathways such as glycolysis, the Krebs cycle and fatty acid synthesis, for example,” highlights Sandra Martha Gomes Dias, a researcher at the National Center for Research in Energy and Materials (CNPEM) supported by FAPESP in diverse studies that unravel the role of glutaminase in tumor activity.
Elevated levels of HuR are correlated with increased expression of genes that support cancer cell proliferation and survival, suggesting a poor patient prognosis. Thus, the regulation of this protein may also be a good therapeutic target. “Small molecule inhibitors of HuR have already been identified and new formulations for their targeted delivery to tumor cells have been developed with promising anticancer activity,” Dias emphasizes.
Isoforms
The researchers showed that the HuR protein, which is often overexpressed in several types of cancer, plays a vital role in choosing to produce different forms of the enzyme glutaminase. “When HuR is at reduced levels, it increases the production of the GAC isoform – which converts glutamine into glutamate more quickly,” says Adamoski.
By reducing the expression of HuR, the group was then able to reduce the KGA isoform and increase GAC, making the metabolism of cancer cells even more dependent on glutamine. “By reducing HuR and, at the same time, chemically inhibiting glutaminase, we were able to significantly reduce the growth and invasion of breast cancer cells,” says Adamoski.
Researchers linked to CNPEM, the State University of Campinas (Unicamp), Washington University School of Medicine (United States), University of Medicine Iuliu-Hatieganu (Romania) and the University of Texas (United States) were involved in the study.
The line of research also received other support from FAPESP (20/16030-0, 14/18061-9, 20/09535-8 and 16/06625-0).
The findings suggest that a therapeutic strategy combining glutaminase and HuR inhibition may be a promising approach for the treatment of breast cancer. The work follows another relevant study supported by FAPESP, in which Sandra and Adamoski also participated, with article published in Nature Structural & Molecular Biology.
This previous work helped elucidate glutaminase’s strategies for achieving greater metabolic activity, which is through the formation of filaments within mitochondria. It was an important discovery, then, because dysregulation of tumor metabolism plays a crucial role in cancer progression and metastasis, and is associated with a worse prognosis in breast cancer patients.
This content was originally published in Breast cancer: strategy acts against enzyme that “feeds” tumor on the CNN Brasil website.