Arboretto, Paola (2023) Interfering with GADD45β-MKK7 survival complex in anaplastic thyroid carcinoma. [Tesi di dottorato]
Anteprima |
Testo
Arboretto_Paola_XXXV.pdf Download (4MB) | Anteprima |
| Tipologia del documento: | Tesi di dottorato |
|---|---|
| Lingua: | English |
| Titolo: | Interfering with GADD45β-MKK7 survival complex in anaplastic thyroid carcinoma |
| Autori: | Autore Email Arboretto, Paola paola.arboretto@unina.it |
| Data: | 10 Marzo 2023 |
| Numero di pagine: | 81 |
| Istituzione: | Università degli Studi di Napoli Federico II |
| Dipartimento: | Medicina Molecolare e Biotecnologie Mediche |
| Dottorato: | Medicina molecolare e biotecnologie mediche |
| Ciclo di dottorato: | 35 |
| Coordinatore del Corso di dottorato: | nome email Santoro, Massimo masantor@unina.it |
| Tutor: | nome email Leonardi, Antonio [non definito] |
| Data: | 10 Marzo 2023 |
| Numero di pagine: | 81 |
| Parole chiave: | NF-κB, thyroid cancer, GADD45β |
| Settori scientifico-disciplinari del MIUR: | Area 06 - Scienze mediche > MED/04 - Patologia generale |
| Depositato il: | 21 Mar 2023 10:34 |
| Ultima modifica: | 09 Apr 2025 13:13 |
| URI: | http://www.fedoa.unina.it/id/eprint/15036 |
Abstract
The alteration of the apoptotic machinery is an essential hallmark of cancer. Transcription factors belonging to NF-κB family play a crucial role orchestrating the balance of many apoptotic genes. Among the anti-apoptotic NF-κB effectors, GADD45β exerts a pivotal function hampering apoptosis and promoting cell survival. Alterations in GADD45β expression correlate with negative prognosis and worse outcome in several human malignancies. Therefore, GADD45β represented an attractive therapeutic target leading to the development of the first-in-class inhibitor DTP3 in Multiple Myeloma. Indeed, DTP3 showed to interfere with GADD45β aberrant activity with high efficacy and cancer-specificity. The purpose of this study was to investigate DTP3 biological efficacy in anaplastic thyroid carcinoma (ATC) with high GADD45β expression levels. For this purpose, ATC cell lines were screened for GADD45β expression levels and characterized for DTP3 dose-response assays. The results showed DTP3 effective permeability and biological activity in ATC cell lines. Accordingly, IC50 values revealed the correlation between GADD45β expression levels and DTP3 efficacy. Moreover, proliferation and apoptosis assays on DTP3-responsive cell lines demonstrated that DTP3 triggers cell cycle arrest followed by delayed apoptosis. Thus, the results revealed that DTP3 affects MAPK/ERK pathway followed by JNK signaling activation. Strikingly, RNA-seq data analysis unveiled that DTP3 treatment prompts reticulum endoplasmic (ER) stress response altering ER genes expression levels. Overall, these findings demonstrate DTP3 specificity and efficacy in ATC cell lines expressing high Gadd45β levels via a novel mechanism that involves ER stress response and eventually the activation of apoptotic pathway.
Downloads
Downloads per month over past year
Actions (login required)
 |
Modifica documento |
