Mechanistic elucidation of the antitumor properties of withaferin a in breast cancer.

Abstract

Withaferin A (WFA) is a steroidal lactone with antitumor effects manifested at multiple levels that are mechanistically obscure. Using a phospho-kinase screening array, we discovered that WFA activated phosphorylation of the S6 kinase RSK (ribosomal S6 kinase) in breast cancer cells. Pursuing this observation, we defined activation of extracellular signal-regulated kinase (ERK)-RSK and ETS-like transcription factor 1 (Elk1)-CHOP (C-EBP homologous protein) kinase pathways in upregulating transcription of the death receptor 5 (DR5). Through this route, WFA acted as an effective DR5 activator capable of potentiating the biologic effects of celecoxib, etoposide, and TRAIL. Accordingly, WFA treatment inhibited breast tumor formation in xenograft and mouse mammary tumor virus (MMTV)-neu mouse models in a manner associated with activation of the ERK/RSK axis, DR5 upregulation, and elevated nuclear accumulation of Elk1 and CHOP. Together, our results offer mechanistic insight into how WFA inhibits breast tumor growth.

• Authors: Arumugam Nagalingam, Panjamurthy Kuppusamy, Shivendra V Singh, Dipali Sharma, Neeraj K Saxena
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 9 Pg. 2617-29 (May 01 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24732433 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 AACR.

Chemical References

• Antineoplastic Agents, Hormonal
• DDIT3 protein, human
• ELK1 protein, human
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Withanolides
• ets-Domain Protein Elk-1
• Transcription Factor CHOP
• Ribosomal Protein S6 Kinases, 90-kDa
• withaferin A

Topics

• Animals
• Antineoplastic Agents, Hormonal (pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Nucleus (metabolism)
• Cell Survival (drug effects)
• Female
• Humans
• MAP Kinase Signaling System
• MCF-7 Cells
• Mice
• Mice, Nude
• Phosphorylation
• Protein Processing, Post-Translational (drug effects)
• Protein Transport
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Ribosomal Protein S6 Kinases, 90-kDa (metabolism)
• Transcription Factor CHOP (metabolism)
• Tumor Burden (drug effects)
• Withanolides (pharmacology)
• Xenograft Model Antitumor Assays
• ets-Domain Protein Elk-1 (metabolism)