PMID- 21040686
OWN - NLM
STAT- MEDLINE
DCOM- 20110622
LR  - 20151119
IS  - 1603-9629 (Electronic)
IS  - 0907-8916 (Linking)
VI  - 57
IP  - 10
DP  - 2010 Oct
TI  - Role of tumor necrosis factor-alpha in the regulation of keratinocyte cell cycle and 
      DNA repair after ultraviolet-B radiation.
PG  - B4179
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine produced in the 
      skin in response to ultraviolet B radiation (UVB). TNF-alpha facilitates UVB-induced 
      apoptosis and probably contributes to removal of damaged cells. Surprisingly, 
      murine TNF-alpha-knockout models have demonstrated that TNF-alpha is necessary for the 
      early stages of skin carcinogenesis and development of squamous cell carcinoma. 
      In the present PhD thesis, we examined the effects of TNF-alpha on DNA repair and 
      cell cycle regulation in UVB-irradiated keratinocytes. In the model of 
      premalignant keratinocytes (HaCaT), TNF-alpha abolished the UVB-induced G2/M 
      checkpoint and diminished the DNA repair despite induction of apoptosis. TNF-alpha 
      activated the protein kinase B/Akt and regulation of its downstream targets, 
      mTOR, Bad and FoxO3a. This effect was dependent on atypical protein kinase C 
      species (aPKC) since a specific peptide blocking the activity of the PKCxi and iota/lambda 
      abrogated the activation of Akt by TNF-alpha. The aPKC-Akt axis was likely to be 
      responsible for the TNF-alpha-induced decrease in DNA repair since blocking of Akt 
      activity restored DNA repair. Since anti-TNF-alpha approaches are increasingly used 
      in the therapy of autoimmune diseases and one of the safety concerns is the 
      potential enhancement of skin carcinogenesis, we investigated the effect of the 
      chimeric monoclonal anti-TNF-alpha antibody infliximab on UVB-irradiated HaCaT cells. 
      Cells treated with infliximab had significantly increased levels of DNA damage 
      despite enhanced G2/M checkpoint arrest, increased apoptosis and inhibition of 
      Akt. In conclusion, we identified a possible novel mechanism by which TNF-alpha 
      promotes UVB-induced skin carcinogenesis. This depends on aPKC-Akt activation and 
      inhibition of DNA repair. TNF-alpha-treated cells are prone to escape checkpoint 
      control and are possibly more likely to accumulate mutations, which may 
      constitute a relevant mechanism enhancing tumor development. The effect of 
      anti-TNF-alpha therapy on skin carcinogenesis warrants further investigation as our 
      study indicates that, in contrast to what had been expected, infliximab may 
      impair DNA repair.
FAU - Faurschou, Annesofie
AU  - Faurschou A
AD  - Department of Dermatology, D92, Bispebjerg Hospital, University of Copenhagen, 
      Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark. annesofie79@yahoo.dk
LA  - eng
PT  - Journal Article
PT  - Review
PL  - Denmark
TA  - Dan Med Bull
JT  - Danish medical bulletin
JID - 0066040
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Dermatologic Agents)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - B72HH48FLU (Infliximab)
SB  - IM
MH  - Antibodies, Monoclonal/therapeutic use
MH  - Apoptosis
MH  - Apoptosis Regulatory Proteins
MH  - Cell Cycle/*radiation effects
MH  - DNA Damage/genetics
MH  - DNA Repair/*radiation effects
MH  - Dermatologic Agents/therapeutic use
MH  - Humans
MH  - Infliximab
MH  - Keratinocytes/*cytology/radiation effects
MH  - Reactive Oxygen Species
MH  - Receptors, Tumor Necrosis Factor/*physiology
MH  - Signal Transduction
MH  - *Tumor Necrosis Factor-alpha
MH  - Ultraviolet Rays/*adverse effects
EDAT- 2010/11/03 06:00
MHDA- 2011/06/23 06:00
CRDT- 2010/11/03 06:00
PHST- 2010/11/03 06:00 [entrez]
PHST- 2010/11/03 06:00 [pubmed]
PHST- 2011/06/23 06:00 [medline]
AID - B4179 [pii]
PST - ppublish
SO  - Dan Med Bull. 2010 Oct;57(10):B4179.