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Ursodeoxycholic Acid Inhibits Glioblastoma Progression via Endoplasmic Reticulum Stress Related Apoptosis and Synergizes with the Proteasome Inhibitor Bortezomib
journal contribution
posted on 2020-04-09, 12:05 authored by Zhong Yao, Xun Zhang, Feihu Zhao, Shuai Wang, Anjing Chen, Bin Huang, Jian Wang, Xingang LiUrsodeoxycholic
acid (UDCA) has demonstrated cancer suppressive
potential in several tumors. Here, we investigated the antitumor potential
and biochemical mechanism of UDCA on glioblastoma multiforme (GBM),
the deadliest form of brain cancer with a median survival of 15 months.
Cell viability was assessed using the CCK-8 and colony forming assays.
Expression profiles were obtained using RNA sequencing, and PCR and
Western blot were used to validate changes in related markers at the
RNA and protein levels. Flow cytometry was used to examine cell cycle,
apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen
species (ROS). UDCA inhibited GBM cell viability in a dose- and time-dependent
manner. Flow cytometry demonstrated that cells were arrested in the
G1 phase and underwent apoptosis. The RNA sequencing results showed
UDCA treatment in part targeted gene expression related to mitochondria
and endoplasmic reticulum (ER). UDCA indeed led to decreased MMP,
overproduction of ROS, and ER stress. Three critical ER stress sensors
ATF6, IRE1α, and PERK were increased in the acute phase. Additionally,
combining UDCA with the proteasome inhibitor bortezomib (BTZ) achieved
a synergistic effect through enhancing the PERK/ATF4/CHOP pathway
and protracting ER stress. UDCA inhibited GBM progression, and the
combination with BTZ achieved a synergistic effect via protracted
ER stress. Thus, UDCA, alone or with combination of BTZ, shows promise
as a possible therapeutic agent for the treatment of GBM.
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UDCACCKRNA sequencing resultsER stressPERKprotracting ER stressProteasome Inhibitor Bortezomib Ursodeoxycholic acidproteasome inhibitor bortezomibG 1 phasePCRflow cytometryEndoplasmic Reticulum Stress Related ApoptosisROSreactive oxygen speciesATFGBM cell viabilityMMPBTZInhibits Glioblastoma ProgressionIRE
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