PMID- 22890326
OWN - NLM
STAT- MEDLINE
DCOM- 20130906
LR  - 20220129
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 32
IP  - 27
DP  - 2013 Jul 4
TI  - The mTOR inhibitor rapamycin opposes carcinogenic changes to epidermal Akt1/PKBalpha 
      isoform signaling.
PG  - 3254-62
LID - 10.1038/onc.2012.338 [doi]
AB  - Epidermal squamous cell carcinoma (SCC) is the most aggressive non-melanoma skin 
      cancer and is dramatically increased in patients undergoing immunosuppression 
      following solid organ transplantation, contributing substantially to morbidity 
      and mortality. Recent clinical studies show that use of the mammalian target of 
      rapamycin (mTOR) inhibitor rapamycin as a post-transplantation immunosuppressive 
      significantly reduces SCC occurrence compared with other immunosuppressives, 
      though the mechanism is not fully understood. We show that rapamycin selectively 
      upregulates epidermal Akt1, while failing to upregulate epidermal Akt2. Rapamycin 
      increases epidermal Akt1 phosphorylation via inhibition of the mTOR complex 
      1-dependent regulation of insulin receptor substrate-1. Epidermal Akt1 is 
      commonly downregulated in SCC while Akt2 is upregulated. We now demonstrate 
      similar Akt1 downregulation and Akt2 upregulation by ultraviolet (UV) radiation, 
      the most important skin carcinogen. Hence, rapamycin's upregulation of Akt1 
      signaling could potentially oppose the effects of UV radiation and/or 
      tumor-associated changes on Akt1 signaling. We show in skin culture that 
      rapamycin does enhance restoration of Akt1 phosphorylation in skin recovering 
      from UV radiation, suggesting a mechanism for rapamycin's antitumor activity in 
      epidermis in spite of its efficient immunosuppressive properties.
FAU - Sully, K
AU  - Sully K
AD  - Centre for Cutaneous Research, Blizard Institute, Barts and The London School of 
      Medicine and Dentistry, Queen Mary University of London, London, UK.
FAU - Akinduro, O
AU  - Akinduro O
FAU - Philpott, M P
AU  - Philpott MP
FAU - Naeem, A S
AU  - Naeem AS
FAU - Harwood, C A
AU  - Harwood CA
FAU - Reeve, V E
AU  - Reeve VE
FAU - O'Shaughnessy, R F
AU  - O'Shaughnessy RF
FAU - Byrne, C
AU  - Byrne C
LA  - eng
GR  - 13044/CRUK_/Cancer Research UK/United Kingdom
GR  - MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120813
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Isoenzymes)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Agammaglobulinaemia Tyrosine Kinase
MH  - Animals
MH  - Blotting, Western
MH  - Cell Line
MH  - Cell Transformation, Neoplastic/*drug effects
MH  - Epidermis/*drug effects/metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Immunoprecipitation
MH  - Immunosuppressive Agents/*pharmacology
MH  - Isoenzymes/metabolism
MH  - Keratinocytes/drug effects/metabolism
MH  - Mice
MH  - Phosphorylation
MH  - Protein-Tyrosine Kinases/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*drug effects/physiology
MH  - Sirolimus/*pharmacology
MH  - Skin
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - Ultraviolet Rays
EDAT- 2012/08/15 06:00
MHDA- 2013/09/07 06:00
CRDT- 2012/08/15 06:00
PHST- 2011/10/18 00:00 [received]
PHST- 2012/05/17 00:00 [revised]
PHST- 2012/06/24 00:00 [accepted]
PHST- 2012/08/15 06:00 [entrez]
PHST- 2012/08/15 06:00 [pubmed]
PHST- 2013/09/07 06:00 [medline]
AID - onc2012338 [pii]
AID - 10.1038/onc.2012.338 [doi]
PST - ppublish
SO  - Oncogene. 2013 Jul 4;32(27):3254-62. doi: 10.1038/onc.2012.338. Epub 2012 Aug 13.