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

Karine Z. Oben, Sara S. Alhakeem, Mary K. McKenna, Jason A. Brandon, Rajeswaran Mani, Sunil K. Noothi, Liu Jinpeng, Shailaja Akunuru, Sanjit K. Dhar, Inder P. Singh, Ying Liang, Chi Wang, Ahmed Abdel-Latif, Harold F. Stills, Daret K. St. Clair, Hartmut Geiger, Natarajan Muthusamy, Kaoru Tohyama, Ramesh C. Gupta, Subbarao Bondada

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)77436-77452
Number of pages17
JournalOncotarget
Volume8
Issue number44
DOIs
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© Oben et al.

Keywords

  • Apoptosis
  • JNK/AP-1 signaling
  • Myelodysplastic syndrome (MDS)
  • Withaferin A (WFA)
  • reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Oxidative stress-induced JNK/AP-1 signaling is a major pathway involved in selective apoptosis of myelodysplastic syndrome cells by Withaferin-A'. Together they form a unique fingerprint.

Cite this