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Anticancer potential of UDCA on GBM

ABSTRACT: Glioblastoma multiforme (GBM) is the deadliest form of brain tumor with a median survival time of 15 months due to drug resistance. Ursodeoxycholic acid (UDCA) is approved of cancer suppressive potential in several tumors. Here we researched on the antitumor potential of UDCA on GBM. The CCK-8 and colony formation was used for detecting cell viability. RNA sequencing hinted transcriptional profile and pathways. PCR and western blot tested the change of related markers. Phenotype changes as cell cycle, apoptosis, MMP and ROS were measured. UDCA inhibited GBM cell viability in a dose- and time-dependent way. RNA sequencing results exhibited UDCA treatment was related to glioma progression and located on mitochondria and endoplasmic reticulum (ER). Cell cycle was arrested in G1 phase followed by caspase-independent apoptosis. UDCA led to decreased MMP, overproduction of ROS and ER stress. Three main stress sensors ATF6, IRE1αand PERK were activated in acute phase. Combining UDCA with bortezomib achieved a synergistic effect via enhancing PERK/ATF4/CHOP pathway and alleviating IRE1α activation. UDCA inhibited GBM progression and the combination with bortezomib achieved a synergistic effect via protracted ER stress. UDCA, alone or with combination of BTZ, presented a promising drug for GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143798 | GEO | 2020/01/17

REPOSITORIES: GEO

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Anticancer potential of UDCA on GBM

Project description:Anticancer potential of UDCA on GBM

| PRJNA601733 | ENA

Expression data from menadione, PERK inhibitor, or control-treated HMLE-shGFP and HMLE-Twist human mammary epithelial cells

Project description:Malignant carcinomas that recur following therapy are typically de-differentiated and multi-drug resistant (MDR). De-differentiated cancer cells acquire MDR by upregulating reactive oxygen species (ROS)-scavenging enzymes and drug efflux pumps, but how these genes are upregulated in response to de-differentiation is not known. Here, we examine this question by using global transcriptional profiling to identify ROS-induced genes that are already upregulated in de-differentiated cells, even in the absence of oxidative damage. Using this approach, we found that the Nrf2 transcription factor, which is the master regulator of cellular response to oxidative stress, is pre-activated in de-differentiated cells. In de-differentiated cells, Nrf2 is not activated by oxidation but rather through a non-canonical mechanism involving its phosphorylation by the ER membrane kinase PERK. In contrast, differentiated cells require oxidative damage to activate Nrf2. Constitutive PERK-Nrf2 signaling protects de-differentiated cells from chemotherapy by reducing ROS levels and increasing drug efflux. These findings are validated in therapy-resistant basal breast cancer cell lines and animal models, where inhibition of the PERK-Nrf2 signaling axis reversed the MDR of de-differentiated cancer cells. Additionally, analysis of patient tumor datasets showed that a PERK pathway signature correlates strongly with chemotherapy resistance, tumor grade, and overall survival. Collectively, these results indicate that de-differentiated cells upregulate MDR genes via PERK-Nrf2 signaling, and suggest that targeting this pathway could sensitize drug-resistant cells to chemotherapy. Differentiated human breast epithelial cells (HMLE-shGFP) or de-differentiated cells (HMLE-Twist) were treated in culture with 40uM menadione for 2 hours or 1uM PERK inhibitor for 48 hours and compared to control DMSO-treated cells.

2014-10-01 | E-GEOD-59780 | biostudies-arrayexpress

Dual role of the unfolded protein response in the therapeutic effect of AZD1775 on TP53 mutant high grade serous ovarian cancer

Project description:we demonstrate that the WEE1 inhibitor AZD1775 triggers endoplasmic reticulum (ER) stress and activates the PERK and IRE1α branches of the unfolded protein response (UPR) in TP53 mutant HGSOC cells. Upon AZD1775 treatment, PERK facilitates apoptotic signaling in these cells via activating CHOP, whereas IRE1α-induced spliced XBP1 (XBP1s) confers survival in response to WEE1 inhibition. Our data uncover an important dual role of UPR in TP53 mutant HGSOC cells in response to AZD1775, where additional inhibition of IRE1α-XBP1s signaling may offer synergistic efficacy.

2021-02-10 | GSE166417 | GEO

Expression data from menadione, PERK inhibitor, or control-treated HMLE-shGFP and HMLE-Twist human mammary epithelial cells

2014-10-01 | GSE59780 | GEO

The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress

Project description:Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK. 14 gene expression arrays, 3 WT control arrays; 3 lsPERK control arrays; 4 WT Treated arrays; 4 lsPERK treated arrays. Comparison of gene expression profiles for treated vs control in wildtype and knock-out.

2012-01-20 | E-GEOD-29929 | biostudies-arrayexpress

The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress

2012-01-20 | GSE29929 | GEO

Neurons shift translational control to secure proteostatic resilience during ER stress

Project description:Proteostasis is essential for survival and particularly important for highly specialized post mitotic cells like neurons. Transient reduction of protein synthesis by protein kinase R–like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. We employed PERK-deficient neuron and astrocyte monocultures to investigate the mechanisms underlying neuron-specific ER stress resilience in the absence of PERK.

2022-06-13 | GSE200742 | GEO

Gene expression profiles of control or PERK siRNA-transfected brown adipocyte during the differentiation

Project description:The area of mitochondria in differentiated brown adipocytes is dramatically increased compared with that in brown pre-adipocytes. The ATP production is switched from the glycolysis pathway to the OXPHOS pathway during brown adipocyte differentiation. Endoplasmic reticulum (ER) is surrounded by mitochondria and the area of contact sites between mitochondria and the ER is increased. ER stress sensor PERK was phosphorylated during differentiation. To elucidate the mitochondria-ER crosstalk signaling mediated by PERK, RNA-sequencing analysis was performed using control siRNA- or PERK siRNA-transfected brown adipocytes.

2020-02-03 | GSE132598 | GEO

PERK is a critical metabolic hub for immunosuppressive function in macrophages

Project description:Here we report that the Th2 cytokine IL-4 and the tumor microenvironment activated protein kinase RNA-like ER kinase (PERK) ER stress signaling cascade to promote immunosuppressive M2 activation and proliferation. Lacking PERK signaling impeded mitochondrial respiration and lipid oxidation critical for M2 macrophages. In addition, PERK activation mediated the upregulation of PSAT1 and serine biosynthesis via the downstream transcription factor ATF4.

2022-01-01 | GSE165836 | GEO

Epigenetic silencing of the tumor suppressor RASSF4 favors multiple myeloma progression

Project description:RAS is frequently mutated in multiple myeloma (MM) leading to aberrant signaling. Next to their classical oncogenic effects, RAS proteins also mediate anti-tumor effects through the Ras-Association Domain Family (RASSF) proteins. Currently, no data about the role of RASSF proteins in MM disease is available. Here we report that RASSF4 is downregulated during MM progression, correlating with a bad prognosis. Epigenetic modulating agents significantly increased RASSF4 expression, indicating that the RASSF4 downregulation is due to epigenetic silencing. Forced RASSF4 expression induced a G2-phase arrest and caspase-3 mediated apoptosis in human MM cell lines, strongly reduced viability of primary CD138+ MM cells and significantly reduced in vivo tumor growth. Moreover, we demonstrated RASSF4-MST1 binding and the involvement of the downstream signaling pathways JNK/Jun, p38 and p53. RASSF4 overexpression sensitized MM cells to the proteasome inhibitor bortezomib, the specific MEK1/2 inhibitor trametinib and the ROS inducer Prima-1Met. Consequently, combining trametinib with histone deacetylase inhibitors (HDACi) revealed very strong synergistic anti-MM activity. In conclusion, our study identified RASSF4 as a new potent tumor suppressor in MM that is epigenetically silenced during MM progression and provides the basis for novel therapeutic strategies enhancing RASSF4 expression (using HDACi) in combination with MEK/ERK inhibitors and bortezomib.

2017-07-31 | GSE85020 | GEO

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