| Full text | |
| Author(s): |
Adamoski, Douglas
;
M. dos Reis, Larissa
;
Mafra, Ana Carolina Paschoalini
;
Correa-da-Silva, Felipe
;
de Moraes-Vieira, Pedro Manoel Mendes
;
Berindan-Neagoe, Ioana
;
Calin, George A.
;
Dias, Sandra Martha Gomes
Total Authors: 8
|
| Document type: | Journal article |
| Source: | NATURE COMMUNICATIONS; v. 15, n. 1, p. 20-pg., 2024-07-04. |
| Abstract | |
Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and drives cells towards glutamine dependence. Furthermore, we show that combining chemical inhibition of GLS with ELAVL1 silencing synergistically decreases breast cancer cell growth and invasion. These findings suggest that dual inhibition of GLS and HuR offers a therapeutic strategy for breast cancer treatment. Changes in the expression of the RNA-binding protein HuR are common in several cancers. Here, the authors show that HuR regulates glutaminase mRNA metabolism in the context of breast cancer. This work reveals that dual inhibition of HuR and glutaminase may have therapeutic potential. (AU) | |
| FAPESP's process: | 14/17820-3 - Post-transcriptional regulation of glutaminase enzyme by HuR and its relationship with high glutaminolytic levels in tumors |
| Grantee: | Douglas Adamoski Meira |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |
| FAPESP's process: | 20/09535-8 - Modulation of mitochondrial dynamics as an approach for macrophage repolarization in cancer treatment |
| Grantee: | Larissa Menezes dos Reis |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 15/25832-4 - Metabolic regulation of genetic and epigenetic control of gene expression |
| Grantee: | Sandra Martha Gomes Dias |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 14/15968-3 - Understanding the glutaminase functional regulation and the development of inhibitors as new approaches to cancer therapy |
| Grantee: | Sandra Martha Gomes Dias |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 21/05726-6 - Metabolism in the microenvironment and the role of metabolic exchanges in tumor progression |
| Grantee: | Sandra Martha Gomes Dias |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 14/18061-9 - Study of alternative anaplerotic sources of the TCA as new targets against triple-negative breast cancer |
| Grantee: | Larissa Menezes dos Reis |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |
| FAPESP's process: | 20/16030-0 - Immunometabolic adaptation of tissue resident macrophages in health and disease |
| Grantee: | Pedro Manoel Mendes de Moraes Vieira |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 16/06625-0 - The mechanisms underlying the GLS2 pro-tumorigenic role |
| Grantee: | Ana Carolina Paschoalini Mafra |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |