Targeting EMT using low-dose Teniposide by downregulating ZEB2-driven activation of RNA polymerase I in breast cancer.

Autor: Metge BJ; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Alsheikh HAM; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Kammerud SC; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Chen D; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Das D; Birmingham VA Health Care System, Birmingham, AL, USA.; Parexel Biotech, Waltham, MA, USA., Nebane NM; High-Throughput Screening Center, Southern Research, Birmingham, AL, USA., Bostwick JR; High-Throughput Screening Center, Southern Research, Birmingham, AL, USA., Shevde LA; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA., Samant RS; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. rsamant@uab.edu.; Birmingham VA Health Care System, Birmingham, AL, USA. rsamant@uab.edu.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. rsamant@uab.edu.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 May 08; Vol. 15 (5), pp. 322. Date of Electronic Publication: 2024 May 08.
DOI: 10.1038/s41419-024-06694-7
Abstrakt: Metastatic dissemination from the primary tumor is a complex process that requires crosstalk between tumor cells and the surrounding milieu and involves the interplay between numerous cellular-signaling programs. Epithelial-mesenchymal transition (EMT) remains at the forefront of orchestrating a shift in numerous cellular programs, such as stemness, drug resistance, and apoptosis that allow for successful metastasis. Till date, there is limited success in therapeutically targeting EMT. Utilizing a high throughput screen of FDA-approved compounds, we uncovered a novel role of the topoisomerase inhibitor, Teniposide, in reversing EMT. Here, we demonstrate Teniposide as a potent modulator of the EMT program, specifically through an IRF7-NMI mediated response. Furthermore, Teniposide significantly reduces the expression of the key EMT transcriptional regulator, Zinc Finger E-Box Binding Homeobox 2 (ZEB2). ZEB2 downregulation by Teniposide inhibited RNA polymerase I (Pol I) activity and rRNA biogenesis. Importantly, Teniposide treatment markedly reduced pulmonary colonization of breast cancer cells. We have uncovered a novel role of Teniposide, which when used at a very low concentration, mitigates mesenchymal-like invasive phenotype. Overall, its ability to target EMT and rRNA biogenesis makes Teniposide a viable candidate to be repurposed as a therapeutic option to restrict breast cancer metastases.
(© 2024. The Author(s).)
Databáze: MEDLINE
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