Oxidative stress-induced JNK/AP-1 signaling is a major pathway involved in selective apoptosis of myelodysplastic syndrome cells by Withaferin-A

Abstract

Myelodysplastic syndromes (MDS) are a diverse group of malignant clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplastic cell morphology in one or more hematopoietic lineages, and a risk of progression to acute myeloid leukemia (AML). Approximately 50% of MDS patients respond to current FDA-approved drug therapies but a majority of responders relapse within 2-3 years. There is therefore a compelling need to identify potential new therapies for MDS treatment. We utilized the MDS-L cell line to investigate the anticancer potential and mechanisms of action of a plant-derived compound, Withaferin A (WFA), in MDS. WFA was potently cytotoxic to MDS-L cells but had no significant effect on the viability of normal human primary bone marrow cells. WFA also significantly reduced engraftment of MDS-L cells in a xenotransplantation model. Through transcriptome analysis, we identified reactive oxygen species (ROS)-activated JNK/AP-1 signaling as a major pathway mediating apoptosis of MDS-L cells by WFA. We conclude that the molecular mechanism mediating selective cytotoxicity of WFA on MDS-L cells is strongly associated with induction of ROS. Therefore, pharmacologic manipulation of redox biology could be exploited as a selective therapeutic target in MDS.

Combination of Withaferin-A and CAPE Provides Superior Anticancer Potency: Bioinformatics and Experimental Evidence to Their Molecular Targets and Mechanism of Action

“…Taken together, these results showed that Wi-A caused oxidative stress leading to ROS generation. This was in line with a previous report that also showed that activation of, c-Jun N-terminal kinase/Activator protein 1 (JNK/AP-1) mediated apoptosis signaling in response to ROS [92]. Other studies have reported that Wi-A induces inhibition of proteasomal degradation resulting in accumulation of ER chaperones (BiP and GRP94) and cytoplasmic heat shock proteins [93].…”

Non-del(5q) myelodysplastic syndromes–associated loci detected by SNP-array genome-wide association meta-analysis

“…Relative gene expression through the JNK pathway, a key mediator of inflammatory signaling in MDS. [33][34][35] Gerstung et al 25 showed that GRID1 expression is significantly (P 5 .013) upregulated (by 0.023) in association with DNMT3A mutations, a commonly found MDS driver mutation that should be explored in the context of the loci identified here. GRID1 introns encode microRNAs critical for unfolded protein response (UPR).…”

The Olive Biophenols Oleuropein and Hydroxytyrosol Selectively Reduce Proliferation, Influence the Cell Cycle, and Induce Apoptosis in Pancreatic Cancer Cells

“…Previously, the forced expression of c-Jun and c-Fos has induced apoptosis in neuronal cells [ 47 , 48 ]. Additionally, treatment of myelodysplastic cells with the plant-derived compound, withaferin A, caused an increase in the mRNA expression of JUN and FOS and their subsequent protein expression and resulted in downstream activation of apoptosis [ 49 ]. More specifically, Ren et al [ 33 ] were able to show that increasing the expression of c-Jun and c-Fos in MIA PaCa-2 cells caused the downstream induction of apoptosis via activation of Bim and the subsequent effect on Bcl-2 family proteins.…”