PMID- 20707922
OWN - NLM
STAT- MEDLINE
DCOM- 20101208
LR  - 20211020
IS  - 1755-8794 (Electronic)
IS  - 1755-8794 (Linking)
VI  - 3
DP  - 2010 Aug 13
TI  - The NRF2-mediated oxidative stress response pathway is associated with tumor cell 
      resistance to arsenic trioxide across the NCI-60 panel.
PG  - 37
LID - 10.1186/1755-8794-3-37 [doi]
AB  - BACKGROUND: Drinking water contaminated with inorganic arsenic is associated with 
      increased risk for different types of cancer. Paradoxically, arsenic trioxide can 
      also be used to induce remission in patients with acute promyelocytic leukemia 
      (APL) with a success rate of approximately 80%. A comprehensive study examining 
      the mechanisms and potential signaling pathways contributing to the anti-tumor 
      properties of arsenic trioxide has not been carried out. METHODS: Here we applied 
      a systems biology approach to identify gene biomarkers that underlie tumor cell 
      responses to arsenic-induced cytotoxicity. The baseline gene expression levels of 
      14,500 well characterized human genes were associated with the GI50 data of the 
      NCI-60 tumor cell line panel from the developmental therapeutics program (DTP) 
      database. Selected biomarkers were tested in vitro for the ability to influence 
      tumor susceptibility to arsenic trioxide. RESULTS: A significant association was 
      found between the baseline expression levels of 209 human genes and the 
      sensitivity of the tumor cell line panel upon exposure to arsenic trioxide. These 
      genes were overlayed onto protein-protein network maps to identify 
      transcriptional networks that modulate tumor cell responses to arsenic trioxide. 
      The analysis revealed a significant enrichment for the oxidative stress response 
      pathway mediated by nuclear factor erythroid 2-related factor 2 (NRF2) with high 
      expression in arsenic resistant tumor cell lines. The role of the NRF2 pathway in 
      protecting cells against arsenic-induced cell killing was validated in tumor 
      cells using shRNA-mediated knock-down. CONCLUSIONS: In this study, we show that 
      the expression level of genes in the NRF2 pathway serve as potential gene 
      biomarkers of tumor cell responses to arsenic trioxide. Importantly, we 
      demonstrate that tumor cells that are deficient for NRF2 display increased 
      sensitivity to arsenic trioxide. The results of our study will be useful in 
      understanding the mechanism of arsenic-induced cytotoxicity in cells, as well as 
      the increased applicability of arsenic trioxide as a chemotherapeutic agent in 
      cancer treatment.
FAU - Liu, Qian
AU  - Liu Q
AD  - Department of Environmental Sciences and Engineering, Gillings School of Global 
      Public Health, University of North Carolina, Chapel Hill, NC, USA.
FAU - Zhang, Hao
AU  - Zhang H
FAU - Smeester, Lisa
AU  - Smeester L
FAU - Zou, Fei
AU  - Zou F
FAU - Kesic, Matt
AU  - Kesic M
FAU - Jaspers, Ilona
AU  - Jaspers I
FAU - Pi, Jingbo
AU  - Pi J
FAU - Fry, Rebecca C
AU  - Fry RC
LA  - eng
GR  - P30 ES010126/ES/NIEHS NIH HHS/United States
GR  - ES016005/ES/NIEHS NIH HHS/United States
GR  - T32 ES007126/ES/NIEHS NIH HHS/United States
GR  - P30-ES10126/ES/NIEHS NIH HHS/United States
GR  - P42 ES005948/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100813
PL  - England
TA  - BMC Med Genomics
JT  - BMC medical genomics
JID - 101319628
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Arsenicals)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Oxides)
RN  - S7V92P67HO (Arsenic Trioxide)
SB  - IM
MH  - Antineoplastic Agents/*toxicity
MH  - Arsenic Trioxide
MH  - Arsenicals
MH  - Biomarkers, Tumor/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Humans
MH  - Leukemia, Promyelocytic, Acute/etiology
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - National Cancer Institute (U.S.)
MH  - *Oxidative Stress
MH  - Oxides/*toxicity
MH  - RNA Interference
MH  - United States
PMC - PMC2939609
EDAT- 2010/08/17 06:00
MHDA- 2010/12/14 06:00
PMCR- 2010/08/13
CRDT- 2010/08/17 06:00
PHST- 2010/03/15 00:00 [received]
PHST- 2010/08/13 00:00 [accepted]
PHST- 2010/08/17 06:00 [entrez]
PHST- 2010/08/17 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2010/08/13 00:00 [pmc-release]
AID - 1755-8794-3-37 [pii]
AID - 10.1186/1755-8794-3-37 [doi]
PST - epublish
SO  - BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.