Year: 2025
Type: article
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers.Microtubule inhibition is a promising therapeutic target as microtubule dynamics play a critical role in growth of metastases due to over expression of several β-tubulin subtypes compared to normal cells.Previous studies have shown that decreased expression of βIII-and βIVb-tubulin is associated with decreased PDAC cell growth.Bromodomain and Extra-Terminal domain (BET) proteins are transcription factors that regulate mitochondria proteins.In this study, we hypothesize that SB-216 and Veru-111 (related novel compounds) inhibit cell growth via suppression of oncogenic βIII-and βIVb-tubulin subtypes and mitochondria function via suppression of BRD4, the most active BET protein.PDAC cell growth was analyzed with the IncuCyte Live-Cell Analysis system.mRNA expression of βIII-and βIVb-tubulin was evaluated with quantitative real time PCR.Western blot analysis was performed for βIII, βIVb-tubulin, and BRD4 protein expression and expression of autophagy and mitophagy markers LC3B and p62/SQSTM1.Mitochondrial function/respiration was measured using a Seahorse XF-24 Flux Analyzer.Cell growth was greatly inhibited across all doses in multiple PDAC cell lines (p < .0001).mRNA expression of TUBB3 (βIII subtype) and TUBB4 (βIVb subtype) was significantly decreased (p < .05).BRD4 protein expression was reduced in with compensatory increase in mRNA expression.Treated PDCL had reduced mitochondrial respiration.Autophagy markers were increased in treated PDAC cells.Our data demonstrates that SB-216 effectively inhibits PDAC cell growth through inhibiting oncogenic microtubules and mitochondrial function.This novel approach simultaneously targets two hallmarks of cancer and patient demise.
Source: Oncoscience
Institution: University of Tennessee Health Science Center
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7125780637