Transcriptome-based identification of lovastatin as a breast cancer stem cell-targeting drug
| Autor: | Aliesha González-Arenas, Sonia Mayra Pérez-Tapia, Mireya Velázquez-Paniagua, Sandra L. Guerrero-Rodríguez, Luz X. Vásquez-Bochm, Sandra S. Castro-Vázquez, Marco A. Velasco-Velázquez, Abimael Mondragon-Peralta, Marisol de la Fuente-Granada |
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| Rok vydání: | 2019 |
| Předmět: |
Transcriptional Activation
Down-Regulation Breast Neoplasms Transcriptome Mice 03 medical and health sciences Transactivation Drug Delivery Systems 0302 clinical medicine Breast cancer SOX2 Cell Line Tumor Animals Humans Medicine MTT assay Lovastatin Promoter Regions Genetic Pharmacology business.industry SOXB1 Transcription Factors General Medicine medicine.disease Drug repositioning 030220 oncology & carcinogenesis Neoplastic Stem Cells Cancer research Female lipids (amino acids peptides and proteins) Neoplasm Recurrence Local Stem cell business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Pharmacological Reports. 71:535-544 |
| ISSN: | 1734-1140 |
| DOI: | 10.1016/j.pharep.2019.02.011 |
| Popis: | Background Breast cancer is a neoplastic disease with high morbidity and mortality in women worldwide. Breast cancer stem cells (CSCs) have a significant function in tumor growth, recurrence, and therapeutic resistance. Thus, CSCs have been pointed as targets of new therapies for breast cancer. Herein, we aimed to repurpose certain drugs as breast CSC-targeting agents. Methods We compared a consensus breast CSC signature with the transcriptomic changes that were induced by over 1300 bioactive compounds using Connectivity Map. The effects of the selected drugs on SOX2 promoter transactivation, SOX2 expression, viability, clonogenicity, and ALDH activity in breast cancer cells were analyzed by luciferase assay, western blot, MTT assay, mammosphere formation assay, and ALDEFLUOR® test, respectively. Gene Set Enrichment Analysis (GSEA) was performed using the gene expression data from mammary tumors of mice that were treated with lovastatin. Results Five drugs (fasudil, pivmecillinam, ursolic acid, 16,16-dimethylprostaglandin E2, and lovastatin) induced signatures that correlated negatively with the query CSC signature. In vitro, lovastatin inhibited SOX2 promoter transactivation, and reduced the efficiency of mammosphere formation and the percentage of ALDH+ cells. Mevalonate mitigated the effects of lovastatin, suggesting that the targeting of CSCs by lovastatin was mediated by the inhibition of its reported target, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). By GSEA, lovastatin downregulated genes that are involved in stemness and invasiveness in mammary tumors, corroborating our in vitro findings. Conclusion Lovastatin is a breast CSC-targeting drug. The inhibition of HMGCR might develop new adjuvant therapeutic strategies for breast tumors. |
| Databáze: | OpenAIRE |
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