PMID- 24732433
OWN - NLM
STAT- MEDLINE
DCOM- 20140706
LR  - 20211021
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 74
IP  - 9
DP  - 2014 May 1
TI  - Mechanistic elucidation of the antitumor properties of withaferin a in breast 
      cancer.
PG  - 2617-29
LID - 10.1158/0008-5472.CAN-13-2081 [doi]
AB  - 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.
CI  - (c)2014 AACR.
FAU - Nagalingam, Arumugam
AU  - Nagalingam A
AD  - Authors' Affiliations: Department of Oncology, Johns Hopkins University School of 
      Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 
      Department of Medicine, University of Maryland School of Medicine, Baltimore 
      Maryland; and Department of Pharmacology and Chemical Biology, University of 
      Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 
      Pittsburgh, Pennsylvania.
FAU - Kuppusamy, Panjamurthy
AU  - Kuppusamy P
FAU - Singh, Shivendra V
AU  - Singh SV
FAU - Sharma, Dipali
AU  - Sharma D
FAU - Saxena, Neeraj K
AU  - Saxena NK
LA  - eng
GR  - R01 CA131294/CA/NCI NIH HHS/United States
GR  - R21 CA155686/CA/NCI NIH HHS/United States
GR  - R03DK089130/DK/NIDDK NIH HHS/United States
GR  - R01 CA142604/CA/NCI NIH HHS/United States
GR  - R03 DK089130/DK/NIDDK NIH HHS/United States
GR  - K01 DK077137/DK/NIDDK NIH HHS/United States
GR  - K01 DK076742/DK/NIDDK NIH HHS/United States
GR  - R01CA131294/CA/NCI NIH HHS/United States
GR  - K01DK076742/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140414
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents, Hormonal)
RN  - 0 (DDIT3 protein, human)
RN  - 0 (ELK1 protein, human)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Withanolides)
RN  - 0 (ets-Domain Protein Elk-1)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - L6DO3QW4K5 (withaferin A)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Hormonal/*pharmacology
MH  - Breast Neoplasms/*drug therapy/metabolism/pathology
MH  - Cell Nucleus/metabolism
MH  - Cell Survival/drug effects
MH  - Female
MH  - Humans
MH  - MAP Kinase Signaling System
MH  - MCF-7 Cells
MH  - Mice
MH  - Mice, Nude
MH  - Phosphorylation
MH  - Protein Processing, Post-Translational/drug effects
MH  - Protein Transport
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism
MH  - Ribosomal Protein S6 Kinases, 90-kDa/metabolism
MH  - Transcription Factor CHOP/metabolism
MH  - Tumor Burden/drug effects
MH  - Withanolides/*pharmacology
MH  - Xenograft Model Antitumor Assays
MH  - ets-Domain Protein Elk-1/metabolism
PMC - PMC4009451
MID - NIHMS571530
COIS- Conflict of Interest: N/A
EDAT- 2014/04/16 06:00
MHDA- 2014/07/07 06:00
PMCR- 2015/05/01
CRDT- 2014/04/16 06:00
PHST- 2014/04/16 06:00 [entrez]
PHST- 2014/04/16 06:00 [pubmed]
PHST- 2014/07/07 06:00 [medline]
PHST- 2015/05/01 00:00 [pmc-release]
AID - 0008-5472.CAN-13-2081 [pii]
AID - 10.1158/0008-5472.CAN-13-2081 [doi]
PST - ppublish
SO  - Cancer Res. 2014 May 1;74(9):2617-29. doi: 10.1158/0008-5472.CAN-13-2081. Epub 
      2014 Apr 14.