PMID- 18953439
OWN - NLM
STAT- MEDLINE
DCOM- 20081219
LR  - 20211203
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 10
IP  - 11
DP  - 2008 Nov
TI  - Hypoxia-induced energy stress inhibits the mTOR pathway by activating an 
      AMPK/REDD1 signaling axis in head and neck squamous cell carcinoma.
PG  - 1295-302
AB  - The mammalian target of rapamycin (mTOR) signaling network is frequently 
      hyperactivated in patients with head and neck squamous cell carcinoma (HNSCC). 
      Recent studies suggest that hypoxia, a common microenvironmental stress found in 
      tumors, blocks this mitogenic pathway. Here, we demonstrate that in HNSCC cell 
      lines, the expression of the phosphorylated forms of the mTOR downstream targets 
      S6 kinase and S6 (pS6) decreased after hypoxia. These events were associated with 
      a marked up-regulation of the regulated in development and DNA damage 1 (REDD1), 
      a recently characterized hypoxia-induced protein that negatively controls mTOR 
      activity. Conversely, pS6 levels were retained under hypoxia in REDD1 knock-down 
      cells and in HNSCC cells lacking endogenous REDD1 expression. Furthermore, we 
      observed that prolonged hypoxia induced an energy-depleting response as evidenced 
      by decreased cellular ATP levels and AMP-activated protein kinase (AMPK) 
      activation. Interestingly, AMPK inhibition before prolonged hypoxia prevented 
      REDD1 expression, thereby sustaining mTOR activity. These results suggest a novel 
      mechanism by which AMPK activation after hypoxia-induced energy stress may be 
      crucial in regulating REDD1 expression to control the mTOR pathway in HNSCC. 
      Furthermore, we found that, in some HNSCC cells, the reduced mTOR activity in 
      response to hypoxia through AMPK/REDD1 was deregulated, which hence might 
      contribute to the persistent activation of the mTOR pathway in this cancer type.
FAU - Schneider, Abraham
AU  - Schneider A
AD  - Department of Oncology and Diagnostic Sciences, Dental School, University of 
      Maryland, Baltimore, MD 21201, USA. aschneider@umaryland.edu
FAU - Younis, Rania H
AU  - Younis RH
FAU - Gutkind, J Silvio
AU  - Gutkind JS
LA  - eng
GR  - T32 DE007309/DE/NIDCR NIH HHS/United States
GR  - 2T32 DE007309-10A1/DE/NIDCR NIH HHS/United States
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (DDIT4 protein, human)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Carcinoma, Squamous Cell/genetics/*metabolism
MH  - Cell Hypoxia/*physiology
MH  - Cell Line, Tumor
MH  - Gene Expression Regulation, Neoplastic
MH  - Head and Neck Neoplasms/genetics/*metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Protein Kinases/*metabolism
MH  - RNA, Small Interfering
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/genetics/*physiology
PMC - PMC2570606
EDAT- 2008/10/28 09:00
MHDA- 2008/12/20 09:00
CRDT- 2008/10/28 09:00
PHST- 2008/05/14 00:00 [received]
PHST- 2008/08/26 00:00 [revised]
PHST- 2008/08/28 00:00 [accepted]
PHST- 2008/10/28 09:00 [pubmed]
PHST- 2008/12/20 09:00 [medline]
PHST- 2008/10/28 09:00 [entrez]
AID - 08586 [pii]
AID - 10.1593/neo.08586 [doi]
PST - ppublish
SO  - Neoplasia. 2008 Nov;10(11):1295-302. doi: 10.1593/neo.08586.