PMID- 25419573
OWN - NLM
STAT- MEDLINE
DCOM- 20160126
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 11
DP  - 2014
TI  - Tumor necrosis factor-alpha sensitizes breast cancer cells to natural products with 
      proteasome-inhibitory activity leading to apoptosis.
PG  - e113783
LID - 10.1371/journal.pone.0113783 [doi]
LID - e113783
AB  - The inflammatory microenvironment plays an important role in the process of tumor 
      development. Tumor necrosis factor-alpha (TNF-alpha), a key pro-inflammatory cytokine, 
      has a significant role in this process. Natural medicinal products such as 
      Withaferin A (WA) and Celastrol (Cel) have shown anti-cancer and 
      anti-inflammatory properties that can be attributed to multiple mechanisms 
      including, but not limited to, apoptosis induction due to the inhibition of 
      proteasomal activities. This study aimed to investigate the effects of TNF-alpha in 
      combination with WA or Cel in vitro in MDA-MB-231 breast cancer cells. TNF-alpha, 
      when combined with WA or Cel, activated caspase-3 and -9 and downregulated XIAP 
      in a dose-dependent manner, leading to induction of apoptosis in MDA-MB-231 
      breast cancer cells. The combination also caused accumulation of the proteasomal 
      target protein IkappaBalpha, resulting in inhibition of the nuclear translocation of 
      nuclear factor-kappaB (NF-kappaB). Taken together, these results suggest that TNF-alpha could 
      sensitize breast cancer cells MDA-MB-231 to WA and Cel, at least in part, through 
      inhibiting the activation of NF-kappaB signaling, leading to XIAP inhibition with 
      subsequent upregulation of caspase-3 and -9 activities. Thus, the anti-cancer 
      activities of TNF-alpha are enhanced when combined with the natural proteasome 
      inhibitors, WA or Cel.
FAU - Lu, Li
AU  - Lu L
AD  - Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong 
      Province, China; Department of Pathology and Karmanos Cancer Institute, School of 
      Medicine, Wayne State University, Detroit, Michigan, United States of America.
FAU - Shi, Wenli
AU  - Shi W
AD  - Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong 
      Province, China.
FAU - Deshmukh, Rahul R
AU  - Deshmukh RR
AD  - Department of Pathology and Karmanos Cancer Institute, School of Medicine, Wayne 
      State University, Detroit, Michigan, United States of America.
FAU - Long, Jie
AU  - Long J
AD  - Department of Pathology, Guangzhou Medical University, Guangzhou, Guangdong 
      Province, China.
FAU - Cheng, Xiaoli
AU  - Cheng X
AD  - Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong 
      Province, China.
FAU - Ji, Weidong
AU  - Ji W
AD  - Department of Urology, Minimally Invasive Surgery Center, The First Affiliated 
      Hospital of Guangzhou Medical University, Guangdong Provincial Key Laboratory of 
      Urology, Guangzhou, Guangdong Province, China.
FAU - Zeng, Guohua
AU  - Zeng G
AD  - Department of Urology, Minimally Invasive Surgery Center, The First Affiliated 
      Hospital of Guangzhou Medical University, Guangdong Provincial Key Laboratory of 
      Urology, Guangzhou, Guangdong Province, China.
FAU - Chen, Xianliang
AU  - Chen X
AD  - Department of Pathology, Guangzhou Medical University, Guangzhou, Guangdong 
      Province, China.
FAU - Zhang, Yajie
AU  - Zhang Y
AD  - Department of Pathology, Guangzhou Medical University, Guangzhou, Guangdong 
      Province, China.
FAU - Dou, Q Ping
AU  - Dou QP
AD  - Department of Pathology and Karmanos Cancer Institute, School of Medicine, Wayne 
      State University, Detroit, Michigan, United States of America; Departments of 
      Oncology and Pharmacology, School of Medicine, Wayne State University, Detroit, 
      Michigan, United States of America.
LA  - eng
GR  - R21 CA184788/CA/NCI NIH HHS/United States
GR  - 1R01CA20009/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20141124
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Biological Products)
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - 0 (Pentacyclic Triterpenes)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (Triterpenes)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Withanolides)
RN  - 0 (X-Linked Inhibitor of Apoptosis Protein)
RN  - 0 (XIAP protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 9)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - L6DO3QW4K5 (withaferin A)
RN  - L8GG98663L (celastrol)
SB  - IM
MH  - Apoptosis/*drug effects
MH  - Biological Products/*pharmacology
MH  - Blotting, Western
MH  - Breast Neoplasms/genetics/metabolism/pathology
MH  - Caspase 3/metabolism
MH  - Caspase 9/metabolism
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Enzyme Activation/drug effects
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Inhibitor of Apoptosis Proteins/genetics/metabolism
MH  - Microscopy, Fluorescence
MH  - Pentacyclic Triterpenes
MH  - Proteasome Endopeptidase Complex/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Transcription Factor RelA/genetics/metabolism
MH  - Triterpenes/pharmacology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - Withanolides/pharmacology
MH  - X-Linked Inhibitor of Apoptosis Protein/genetics/metabolism
PMC - PMC4242672
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/11/25 06:00
MHDA- 2016/01/27 06:00
PMCR- 2014/11/24
CRDT- 2014/11/25 06:00
PHST- 2014/02/28 00:00 [received]
PHST- 2014/10/02 00:00 [accepted]
PHST- 2014/11/25 06:00 [entrez]
PHST- 2014/11/25 06:00 [pubmed]
PHST- 2016/01/27 06:00 [medline]
PHST- 2014/11/24 00:00 [pmc-release]
AID - PONE-D-14-09339 [pii]
AID - 10.1371/journal.pone.0113783 [doi]
PST - epublish
SO  - PLoS One. 2014 Nov 24;9(11):e113783. doi: 10.1371/journal.pone.0113783. 
      eCollection 2014.