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Wnt inhibitors reduce the unfolded protein response and enhance bortezomib-induced cell death in multiple myeloma

ABSTRACT: Wnt inhibitors reduce the unfolded protein response and enhance bortezomib-induced cell death in multiple myeloma

PROVIDER: PRJNA907219 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22477900_1.fastq.gz	Fastqsanger.gz
	SRR22477900_2.fastq.gz	Fastqsanger.gz
	SRR22477901_1.fastq.gz	Fastqsanger.gz
	SRR22477901_2.fastq.gz	Fastqsanger.gz
	SRR22477902_1.fastq.gz	Fastqsanger.gz

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Wnt inhibitors reduce the unfolded protein response and enhance bortezomib-induced cell death in multiple myeloma

Project description:Dysregulation of the Wnt pathway is involved in pathogenesis of many types of carcinomas and associated with certain hematological cancers, including multiple myeloma (MM). Several studies reported that MM plasma cells carry a functional Wnt/β-catenin signaling pathway that promotes cell survival. Despite new and successful treatment options, MM remains incurable due to clinical, genetic and transcriptomic heterogeneity, which ultimately results in therapy resistance and relapse. We examined the therapeutic potential of targeting the Wnt pathway in patient-derived MM cells. Our results demonstrate that inhibition of tankyrase (TNKSi) and inhibition of porcupine (PORCi), two established methods to block the Wnt pathway in other cell types and malignancies, promotes cell death of primary MM cells. Single-cell RNA sequencing showed that inhibition of Wnt signaling is likely effectuated via downregulation of genes involved in the unfolded protein response (UPR). Combining TNKSi and PORCi with bortezomib resulted in a potent killing of primary MM cells, demonstrating that inhibitors of Wnt signaling might be considered as therapeutic targets in future anti-myeloma combinatorial strategies.

2023-01-01 | GSE219133 | GEO

Wnt inhibitors reduce the unfolded protein response and enhance bortezomib-induced cell death in multiple myeloma.

Project description: Not available

| S-EPMC10111341 | biostudies-literature

Gene expression profiling of HepG2 cell response to bortezomib in combination with nelfinavir or ISRIB, compounds targeting the eIF2a-ATF4 pathway

Project description:We investigate how modulation of the eIF2alpha-ATF4 stress pathway affects hepatoma cell response to bortezomib. Transcriptome profiling revealed that many ATF4 transcriptional target genes are among the highest upregulated genes in bortezomib-treated HepG2 human hepatoma cells. While pharmacological enhancement of the eIF2alpha-ATF4 pathway activity results in the elevation of the activities of all branches of the unfolded protein response (UPR) and sensitizes cells to bortezomib toxicity, the suppression of ATF4 induction delays bortezomib-induced cell death. The pseudokinase TRIB3, an inhibitor of ATF4, is expressed at a high basal level in hepatoma cells and is strongly upregulated in response to bortezomib. Bortezomib treatment leads to a robust enrichment of TRIB3 binding near genes induced by bortezomib and involved in the ER stress response and cell death. Disruption of TRIB3 increases C/EBP-ATF-driven transcription, augments ER stress and cell death in cells exposed to bortezomib, while TRIB3 overexpression enhances the cell survival. Thus, TRIB3, colocalizing with ATF4 and limiting its transcriptional activity, functions as a factor increasing resistance to bortezomib, while pharmacological over-activation of eIF2alpha-ATF4 can overcome the endogenous restraint mechanisms and sensitize cells to bortezomib.

2021-05-24 | GSE166923 | GEO

Unfolded protein response is not predictive for the antimyeloma activity of bortezomib

Project description:Gene expression profile (GEP) was analyzed from cultured bone marrow (BM) samples from patients with bortezomib responsive versus bortezomib resistant myeloma after 6-8 hours incubation in vitro with bortezomib 2 Âµg/ml or with PBS. Case D also had a fresh BM sample taken 75 minutes after IV injection of bortezomib. Comparative gene expression profiling of cultured bone marrow samples from from patients with bortezomib responsive versus bortezomib resistant myeloma after 6-8 hours incubation in vitro with bortezomib 2 Âµg/ml or with PBS.

2013-11-01 | E-GEOD-51940 | biostudies-arrayexpress

ChIP-Seq of TRIB3 and ATF4 in HepG2 cells treated with bortezomib

Project description:The proteasome is an appealing anti-cancer drug target and the proteasome inhibitor bortezomib has been approved for the treatment of certain types of malignancies. However, the molecular mechanisms underlying cancer cell resistance to bortezomib remain poorly understood. The pseudokinase TRIB3, an inhibitor of ATF4, is expressed at a high basal level in hepatoma cells and is strongly upregulated in response to bortezomib. To map genome-wide chromatin binding loci of TRIB3 protein, we fused a Flag tag to endogenous TRIB3 in HepG2 cells and performed ChIP-Seq. The results demonstrate that TRIB3 predominantly colocalizes with ATF4 on chromatin and the proteins reside in genomic regions containing the C/EBP-ATF motif. Bortezomib treatment leads to a robust enrichment of TRIB3 binding near genes induced by bortezomib and involved in the ER stress response and cell death. Disruption of TRIB3 increases C/EBP-ATF-driven transcription, augments ER stress and cell death in cells exposed to bortezomib, while TRIB3 overexpression enhances the cell survival. Thus, TRIB3, colocalizing with ATF4 and limiting its transcriptional activity, functions as a factor increasing resistance to bortezomib, while pharmacological over-activation of eIF2alpha-ATF4 can overcome the endogenous restraint mechanisms and sensitize cells to bortezomib.

2021-05-24 | GSE166958 | GEO

Anti-leukemia activity of bortezomib through GATA2-WT1 axis in acute myeloid leukemia

Project description:GATA2 is a transcription factor essential for hematopoietic differentiation and lymphatic system formation. High expression of GATA2 has been implicated in myelodysplastic syndrome and acute myeloid leukemia. Bortezomib has a good effect in MM. However, the mechanism of bortezomib possesses anti-self-renewal and leukemogenesis in AML is still unclear. Here, we reported that GATA2 and WT1 protein is degraded by bortezomib. The half-life of GATA2 mRNA was obviously shorter in Bortezomib-treated cells. Knockdown of GATA2 by small hairpin RNAs (shRNAs) has potential anti-leukemia activity in leukemic cells. Bortezomib inhibited cell proliferation and induced apoptotic death without activation of caspases pathway. Finally, bortezomib decreased xenograft tumor size in a xenograft leukemia mouse model, and prolonged the survival time in mouse C1498 AML model. Collectively, bortezomib might be a potential treatment for AML.

2021-11-14 | GSE188358 | GEO

A Subset of Genes Can Distinguish between Bortezomib Responsive Versus Bortezomib Resistant Myeloma

2013-11-01 | GSE51940 | GEO

Genome-wide analysis of gene expression in bladder cancer cell lines 253JB-V and UM-UC13 exposed to bortezomib

Project description:We previously showed that the proteasome inhibitor bortezomib (Velcade) induces cell death in a subset of human bladder cancer cell lines. Heat shock protein 72 kDa (Hsp72) is the major cytosolic stress-inducible molecular chaperone, and is thought to protect cells from proteasome inhibition. Here, using whole genome mRNA expression profiling, we identify isoform-specific expression of Hsp72 within a heterogeneous panel of bladder cancer cell lines. Bortezomib induced strong upregulation of both the HSPA1A and HSPA1B isoforms of Hsp72 in 253J B-V and SW780 (HSPA1A-high) cells, whereas only HSPA1B isoform expression was induced in UM-UC10 and UM-UC13 (HSPA1A-low) cells. Bortezomib stimulated the binding of heat shock factor-1 (HSF1) to the HSPA1A promoter much more efficiently in 253JB-V cells than in UM-UC13, but other HSF1 transcriptional targets were induced in all of the cell lines, implicating a specific defect in HSPA1A induction. Methylation-specific PCR revealed that the HSPA1A promoter was selectively methylated in the HSPA1A-low cell lines (UM-UC10 and UM-UC13), and exposure to the chromatin demethylating agent 5-aza-2'-deoxycytidine restored HSPA1A expression. Overexpression of Hsp72 promoted bortezomib resistance in the UM-UC10 and UM-UC13 cells, whereas transient knockdown of HSPA1B sensitized these cells to bortezomib. Exposure to the chemical HSF1 inhibitor KNK-437 promoted bortezomib sensitivity in the 253J B-V cells. Finally, shRNA-mediated stable knockdown of Hsp72 in 253J B-V promoted sensitivity to bortezomib both in vitro and in vivo. Together, our results suggest that a subset of human bladder cancer cells possess epigenetic modifications that shut off the HSPA1A promoter and increases dependency on the HSPA1B isoform to maintain Hsp72 expression. Our data also support the targeting of HSF1 or Hsp72 for use as tools to enhance bortezomib sensitivity in solid tumors.

2013-08-01 | GSE46132 | GEO

Gene expression profile of the human leukemia cell line Reh after treatment with bortezomib, valproic acid or a combination of both.

Project description:New therapy options are required for relapsed B-cell precursor ALL patients in order to improve survival and reduce adverse acute and late effects. We observed a synergistic anti-leukemic activity of concomitant treatment with bortezomib and valproic acid in BCP-ALL cells. In this experiment we aimed to identify the pathways modulated after concomitant treatment with bortezomib and valproic acid. Reh cells treated with either bortezomib, valproic acid, or the combination of both normalized to a untreated control.

2013-02-01 | E-GEOD-41951 | biostudies-arrayexpress

MicroRNA Expression Profile of serum exosomes from Bortezomib-resistant and Bortezomib-response patients in multiple myeloma

Project description:MicroRNA microarray profilling analysis was performed on exosomes derived from serum in patients with myeloma in two conditions of therapeutic efficacy, Bortezomib resistance and Bortezomib response. Bortezomib is approved and widely used treating myeloma.

2016-07-31 | GSE71435 | GEO

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