Triterpenoid derivatives inhibit Gli-mediated transcription in human glioblastoma cell line via direct interaction with Gli1

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00098892%3A_____%2F25%3A10159419" target="_blank" >RIV/00098892:_____/25:10159419 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0021925825023221?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0021925825023221?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jbc.2025.110472" target="_blank" >10.1016/j.jbc.2025.110472</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Triterpenoid derivatives inhibit Gli-mediated transcription in human glioblastoma cell line via direct interaction with Gli1

Popis výsledku v původním jazyce

The evolutionarily important Hedgehog (HH) signaling pathway plays a critical role in the development and progression of multiple solid tumors, such as basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and various gastrointestinal, pulmonary, and brain tumors. The proteins of the Gli (glioma-associated oncogene homologue) family are key mediators of the HH pathway. In the present study, we have focused on triterpenoid derivatives, which have been shown to induce apoptosis and inhibit HH signaling in rhabdomyosarcoma. Utilizing a U-87MG glioblastoma-derived reporter cell line, we screened a structurally diverse library of triterpenoid derivatives to identify potential antagonists of Gli-mediated transcription. We revealed two derivatives that not only selectively inhibited Gli-mediated gene transactivation but also displayed greater potency than the known Gli1 inhibitor GANT61. These compounds also demonstrated dose- and time-dependent inhibition of U-87MG tumor cell proliferation in vitro. Further mechanistic studies provided genetic evidence for the inhibition of the downstream HH pathway by these compounds, via reduced expression of Gli1 and its transcription targets. However, these compounds did not affect the ciliary localization of Smoothened (Smo). Our findings suggest that the observed inhibitory effects are likely due to a direct interaction between our compounds and Gli1.

Název v anglickém jazyce

Triterpenoid derivatives inhibit Gli-mediated transcription in human glioblastoma cell line via direct interaction with Gli1

Popis výsledku anglicky

The evolutionarily important Hedgehog (HH) signaling pathway plays a critical role in the development and progression of multiple solid tumors, such as basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and various gastrointestinal, pulmonary, and brain tumors. The proteins of the Gli (glioma-associated oncogene homologue) family are key mediators of the HH pathway. In the present study, we have focused on triterpenoid derivatives, which have been shown to induce apoptosis and inhibit HH signaling in rhabdomyosarcoma. Utilizing a U-87MG glioblastoma-derived reporter cell line, we screened a structurally diverse library of triterpenoid derivatives to identify potential antagonists of Gli-mediated transcription. We revealed two derivatives that not only selectively inhibited Gli-mediated gene transactivation but also displayed greater potency than the known Gli1 inhibitor GANT61. These compounds also demonstrated dose- and time-dependent inhibition of U-87MG tumor cell proliferation in vitro. Further mechanistic studies provided genetic evidence for the inhibition of the downstream HH pathway by these compounds, via reduced expression of Gli1 and its transcription targets. However, these compounds did not affect the ciliary localization of Smoothened (Smo). Our findings suggest that the observed inhibitory effects are likely due to a direct interaction between our compounds and Gli1.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Biological Chemistry

ISSN

—

e-ISSN

1083-351X

Svazek periodika

301

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

14

Strana od-do

110472

Kód UT WoS článku

001565682800002

EID výsledku v databázi Scopus

2-s2.0-105014501810