Post-transcriptional regulation is an essential determinant of gene expression programs in physiological and pathological conditions. HuR is a RNA-binding protein that orchestrates the stabilization and translation of mRNAs, critical in inflammation and tumor progression, including tumor necrosis factor-alpha (TNF). We identified the low molecular weight compound 15,16-dihydrotanshinone-I (DHTS), well known in traditional Chinese medicine practice, through a validated high throughput screening on a set of anti-inflammatory agents for its ability to prevent HuR:RNA complex formation. We found that DHTS interferes with the association step between HuR and the RNA with an equilibrium dissociation constant in the nanomolar range in vitro (Ki = 3.74 ± 1.63 nM). In breast cancer cell lines, short term exposure to DHTS influences mRNA stability and translational efficiency of TNF in a HuR-dependent manner and also other functional readouts of its post-transcriptional control, such as the stability of selected pre-mRNAs. Importantly, we show that migration and sensitivity of breast cancer cells to DHTS are modulated by HuR expression, indicating that HuR is among the preferential intracellular targets of DHTS. Here, we disclose a previously unrecognized molecular mechanism exerted by DHTS, opening new perspectives to therapeutically target the HuR mediated, post-transcriptional control in inflammation and cancer cells.

Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function / V.G. D'Agostino, P. Lal, B. Mantelli, C. Tiedje, C. Zucal, N. Thongon, M. Gaestel, E. Latorre, L. Marinelli, P. Seneci, M. Amadio, A. Provenzani. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 5:1(2015 Nov 10).

Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function

E. Latorre;P. Seneci;
2015

Abstract

Post-transcriptional regulation is an essential determinant of gene expression programs in physiological and pathological conditions. HuR is a RNA-binding protein that orchestrates the stabilization and translation of mRNAs, critical in inflammation and tumor progression, including tumor necrosis factor-alpha (TNF). We identified the low molecular weight compound 15,16-dihydrotanshinone-I (DHTS), well known in traditional Chinese medicine practice, through a validated high throughput screening on a set of anti-inflammatory agents for its ability to prevent HuR:RNA complex formation. We found that DHTS interferes with the association step between HuR and the RNA with an equilibrium dissociation constant in the nanomolar range in vitro (Ki = 3.74 ± 1.63 nM). In breast cancer cell lines, short term exposure to DHTS influences mRNA stability and translational efficiency of TNF in a HuR-dependent manner and also other functional readouts of its post-transcriptional control, such as the stability of selected pre-mRNAs. Importantly, we show that migration and sensitivity of breast cancer cells to DHTS are modulated by HuR expression, indicating that HuR is among the preferential intracellular targets of DHTS. Here, we disclose a previously unrecognized molecular mechanism exerted by DHTS, opening new perspectives to therapeutically target the HuR mediated, post-transcriptional control in inflammation and cancer cells.
Breast Neoplasms; Cell Line, Tumor; Cytoplasm; Drug Resistance, Neoplasm; ELAV-Like Protein 1; Female; Gene Expression Regulation; Humans; MCF-7 Cells; Phenanthrenes; Polyribosomes; Protein Binding; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA-Binding Proteins; Tumor Necrosis Factor-alpha; Multidisciplinary
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/10 - Biochimica
10-nov-2015
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/524695
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