Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition–resistant triple-negative breast cancer cells
| Autor: | Pedro M. Moraes-Vieira, Marília M. Dias, Douglas Adamoski, Larissa Menezes dos Reis, Carolline Fernanda Rodrigues Ascenção, Sílvio Roberto Consonni, Ariel Mariano Silber, Sandra Martha Gomes Dias, Fábio Malta de Sá Patroni, Felipe Corrêa-da-Silva, Krishina Ratna Sousa de Oliveira, Rodolpho Ornitz Oliveira Souza |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Glutamine Benzeneacetamides Estrogen receptor Triple Negative Breast Neoplasms Mitochondrion Biochemistry 03 medical and health sciences Glutaminase Cell Movement Thiadiazoles Tumor Cells Cultured medicine Humans Carnitine Protein kinase A Molecular Biology Triple-negative breast cancer Cell Proliferation Carnitine O-Palmitoyltransferase 030102 biochemistry & molecular biology Cell growth Chemistry Cell Biology Warburg effect 030104 developmental biology Drug Resistance Neoplasm LIPÍDEOS Cancer research Female Oxidation-Reduction medicine.drug |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP J Biol Chem |
| Popis: | Triple-negative breast cancers (TNBCs) lack progesterone and estrogen receptors and do not have amplified human epidermal growth factor receptor 2, the main therapeutic targets for managing breast cancer. TNBCs have an altered metabolism, including an increased Warburg effect and glutamine dependence, making the glutaminase inhibitor CB-839 therapeutically promising for this tumor type. Accordingly, CB-839 is currently in phase I/II clinical trials. However, not all TNBCs respond to CB-839 treatment, and the tumor resistance mechanism is not yet fully understood. Here we classified cell lines as CB-839–sensitive or –resistant according to their growth responses to CB-839. Compared with sensitive cells, resistant cells were less glutaminolytic and, upon CB-839 treatment, exhibited a smaller decrease in ATP content and less mitochondrial fragmentation, an indicator of poor mitochondrial health. Transcriptional analyses revealed that the expression levels of genes linked to lipid metabolism were altered between sensitive and resistant cells and between breast cancer tissues (available from The Cancer Genome Atlas project) with low versus high glutaminase (GLS) gene expression. Of note, CB-839–resistant TNBC cells had increased carnitine palmitoyltransferase 2 (CPT2) protein and CPT1 activity levels. In agreement, CB-839–resistant TNBC cells mobilized more fatty acids into mitochondria for oxidation, which responded to AMP-activated protein kinase and acetyl-CoA carboxylase signaling. Moreover, chemical inhibition of both glutaminase and CPT1 decreased cell proliferation and migration of CB-839–resistant cells compared with single inhibition of each enzyme. We propose that dual targeting of glutaminase and CPT1 activities may have therapeutic relevance for managing CB-839–resistant tumors. |
| Databáze: | OpenAIRE |
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