PMID- 28968864
OWN - NLM
STAT- MEDLINE
DCOM- 20171220
LR  - 20180511
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Linking)
VI  - 38
IP  - 12
DP  - 2017 Dec 7
TI  - ATM-activated autotaxin (ATX) propagates inflammation and DNA damage in lung 
      epithelial cells: a new mode of action for silica-induced DNA damage?
PG  - 1196-1206
LID - 10.1093/carcin/bgx100 [doi]
AB  - Silica exposure is a common risk factor for lung cancer. It has been claimed that 
      key elements in cancer development are activation of inflammatory cells that 
      indirectly induce DNA damage and proliferative stimuli in respiratory epithelial 
      cells. We studied DNA damage induced by silica particles in respiratory 
      epithelial cells and focused the role of the signaling enzyme autotaxin (ATX). 
      A549 and 16 bronchial epithelial cells (16HBE) lung epithelial cells were exposed 
      to silica particles. Reactive oxygen species (ROS), NOD-like receptor family 
      pyrin domain containing-3 (NLRP3) inflammasome activation, ATX, ataxia 
      telangiectasia mutated (ATM), and DNA damage (gammaH2AX, pCHK1, pCHK2, comet assay) 
      were end points. Low doses of silica induced NLRP3 activation, DNA damage 
      accumulation, and ATM phosphorylation. A novel finding was that ATM induced ATX 
      generation and secretion. Not only silica but also rotenone, camptothecin and 
      H2O2 activated ATX via ATM, suggesting that ATX is part of a generalized ATM 
      response to double-strand breaks (DSBs). Surprisingly, ATX inhibition mitigated 
      DNA damage accumulation at later time points (6-16 h), and ATX transfection 
      caused NLRP3 activation and DNA damage. Furthermore, the product of ATX enzymatic 
      activity, lysophosphatidic acid, recapitulated the effects of ATX transfection. 
      These data indicate an ATM-ATX-dependent loop that propagates inflammation and 
      DSB accumulation, making low doses of silica effective inducers of DSBs in 
      epithelial cells. We conclude that an ATM-ATX axis interconnects DSBs with 
      silica-induced inflammation and propagates these effects in epithelial cells. 
      Further studies of this adverse outcome pathway may give an accurate assessment 
      of the lowest doses of silica that causes cancer.
CI  - (c) The Author 2017. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Zheng, Huiyuan
AU  - Zheng H
AD  - Institute of Environmental Medicine, Karolinska Institutet Box 210, Sweden.
FAU - Hogberg, Johan
AU  - Hogberg J
AD  - Institute of Environmental Medicine, Karolinska Institutet Box 210, Sweden.
FAU - Stenius, Ulla
AU  - Stenius U
AD  - Institute of Environmental Medicine, Karolinska Institutet Box 210, Sweden.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 7631-86-9 (Silicon Dioxide)
RN  - EC 2.7.11.1 (ATM protein, human)
RN  - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
RN  - EC 3.1.4.- (Phosphoric Diester Hydrolases)
RN  - EC 3.1.4.39 (alkylglycerophosphoethanolamine phosphodiesterase)
SB  - IM
MH  - Ataxia Telangiectasia Mutated Proteins/*metabolism
MH  - Cell Line
MH  - DNA Breaks, Double-Stranded/*drug effects
MH  - Humans
MH  - Inflammation/*metabolism
MH  - Phosphoric Diester Hydrolases/*metabolism
MH  - Respiratory Mucosa/drug effects/metabolism/*pathology
MH  - Silicon Dioxide/*toxicity
EDAT- 2017/10/03 06:00
MHDA- 2017/12/21 06:00
CRDT- 2017/10/03 06:00
PHST- 2016/12/19 00:00 [received]
PHST- 2017/09/12 00:00 [accepted]
PHST- 2017/10/03 06:00 [pubmed]
PHST- 2017/12/21 06:00 [medline]
PHST- 2017/10/03 06:00 [entrez]
AID - 4158487 [pii]
AID - 10.1093/carcin/bgx100 [doi]
PST - ppublish
SO  - Carcinogenesis. 2017 Dec 7;38(12):1196-1206. doi: 10.1093/carcin/bgx100.