PMID- 18483250
OWN - NLM
STAT- MEDLINE
DCOM- 20080624
LR  - 20230202
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 10
DP  - 2008 May 15
TI  - Reduced susceptibility to two-stage skin carcinogenesis in mice with low 
      circulating insulin-like growth factor I levels.
PG  - 3680-8
LID - 10.1158/0008-5472.CAN-07-6271 [doi]
AB  - Calorie restriction has been shown to inhibit epithelial carcinogenesis and this 
      method of dietary restriction reduces many circulating proteins, including 
      insulin-like growth factor I (IGF-I). Previously, we identified a relationship 
      between elevated tissue IGF-I levels and enhanced susceptibility to chemically 
      induced skin tumorigenesis. In this study, liver IGF-I-deficient (LID) mice, 
      which have a 75% reduction in serum IGF-I, were subjected to the standard 
      two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthracene as 
      the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We 
      observed a significant reduction in epidermal thickness and labeling index in LID 
      mice treated with either vehicle or TPA. A significant decrease in both tumor 
      incidence and tumor multiplicity was observed in LID mice undergoing two-stage 
      skin carcinogenesis relative to wild-type littermates. Western blot analyses of 
      epidermal extracts revealed reduced activation of both the epidermal growth 
      factor and IGF-I receptors in response to TPA treatment in LID mice. In addition, 
      reduced activation of both Akt and the mammalian target of rapamycin (mTOR) was 
      observed in LID mice following TPA treatment relative to wild-type controls. 
      Signaling downstream of mTOR was also reduced. These data suggest a possible 
      mechanism whereby reduced circulating IGF-I leads to attenuated activation of the 
      Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor 
      promotion, and ultimately, two-stage skin carcinogenesis. The current data also 
      suggest that reduced circulating IGF-I levels which occur as a result of calorie 
      restriction may lead to the inhibition of skin tumorigenesis, at least in part, 
      by a similar mechanism.
FAU - Moore, Tricia
AU  - Moore T
AD  - The University of Texas M. D. Anderson Cancer Center, Science Park-Research 
      Division, Smithville, Texas, USA.
FAU - Carbajal, Steve
AU  - Carbajal S
FAU - Beltran, Linda
AU  - Beltran L
FAU - Perkins, Susan N
AU  - Perkins SN
FAU - Yakar, Shoshana
AU  - Yakar S
FAU - Leroith, Derek
AU  - Leroith D
FAU - Hursting, Stephen D
AU  - Hursting SD
FAU - Digiovanni, John
AU  - Digiovanni J
LA  - eng
GR  - ES007784/ES/NIEHS NIH HHS/United States
GR  - CA16672/CA/NCI NIH HHS/United States
GR  - CA37111/CA/NCI NIH HHS/United States
GR  - ES007247/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Benz(a)Anthracenes)
RN  - 2564-65-0 (7,12-dihydroxymethylbenz(a)anthracene)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - Animals
MH  - Benz(a)Anthracenes/pharmacology
MH  - Cell Proliferation
MH  - Cell Transformation, Neoplastic
MH  - Epidermis/metabolism
MH  - Female
MH  - *Genetic Predisposition to Disease
MH  - Insulin-Like Growth Factor I/*biosynthesis
MH  - Mice
MH  - Models, Biological
MH  - Neoplasms/metabolism
MH  - Protein Kinases/metabolism
MH  - Signal Transduction
MH  - Skin Neoplasms/chemically induced/*genetics/*pathology
MH  - TOR Serine-Threonine Kinases
MH  - Tetradecanoylphorbol Acetate/pharmacology
EDAT- 2008/05/17 09:00
MHDA- 2008/06/25 09:00
CRDT- 2008/05/17 09:00
PHST- 2008/05/17 09:00 [pubmed]
PHST- 2008/06/25 09:00 [medline]
PHST- 2008/05/17 09:00 [entrez]
AID - 68/10/3680 [pii]
AID - 10.1158/0008-5472.CAN-07-6271 [doi]
PST - ppublish
SO  - Cancer Res. 2008 May 15;68(10):3680-8. doi: 10.1158/0008-5472.CAN-07-6271.