PMID- 16267020
OWN - NLM
STAT- MEDLINE
DCOM- 20051222
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 65
IP  - 21
DP  - 2005 Nov 1
TI  - Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of 
      the head and neck.
PG  - 9953-61
AB  - Emerging knowledge on how the dysregulated function of signaling networks 
      contributes to the malignant growth of squamous cell carcinoma of the head and 
      neck (HNSCC) can now be exploited to identify novel mechanism-based anticancer 
      treatments. In this regard, we have observed that persistent activation of the 
      serine/threonine kinase Akt is a frequent event in HNSCC, and that blockade of 
      its upstream kinase, 3'-phosphoinositide-dependent kinase 1, potently inhibits 
      tumor cell growth. Akt promotes cell proliferation by its ability to coordinate 
      mitogenic signaling with energy- and nutrient-sensing pathways that control 
      protein synthesis through the atypical serine/threonine kinase, mammalian target 
      of rapamycin (mTOR). This kinase, in turn, phosphorylates key eukaryotic 
      translation regulators, including p70-S6 kinase and the eukaryotic translation 
      initiation factor, 4E binding protein 1. Indeed, we show here that aberrant 
      accumulation of the phosphorylated active form of S6, the most downstream target 
      of the Akt-mTOR-p70-S6 kinase pathway, is a frequent event in clinical specimens 
      from patients with HNSCC and their derived cell lines. Of interest, this enhanced 
      level of the phosphorylated active form of S6 was rapidly reduced in HNSCC cell 
      lines and HNSCC xenograft models at clinically relevant doses of rapamycin, which 
      specifically inhibits mTOR. Furthermore, we observed that rapamycin displays a 
      potent antitumor effect in vivo, as it inhibits DNA synthesis and induces the 
      apoptotic death of HNSCC cells, ultimately resulting in tumor regression. These 
      findings identify the Akt-mTOR pathway as a potential therapeutic target for 
      HNSCC, and may provide the rationale for the early clinical evaluation of 
      rapamycin and its analogues in patients with HNSCC.
FAU - Amornphimoltham, Panomwat
AU  - Amornphimoltham P
AD  - Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial 
      Research, NIH, Bethesda 20892-4330, USA.
FAU - Patel, Vyomesh
AU  - Patel V
FAU - Sodhi, Akrit
AU  - Sodhi A
FAU - Nikitakis, Nikolaos G
AU  - Nikitakis NG
FAU - Sauk, John J
AU  - Sauk JJ
FAU - Sausville, Edward A
AU  - Sausville EA
FAU - Molinolo, Alfredo A
AU  - Molinolo AA
FAU - Gutkind, J Silvio
AU  - Gutkind JS
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (DNA, Neoplasm)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Apoptosis/drug effects
MH  - Carcinoma, Squamous Cell/*drug therapy/*enzymology/pathology
MH  - Cell Line, Tumor
MH  - DNA, Neoplasm/biosynthesis
MH  - Female
MH  - Head and Neck Neoplasms/*drug therapy/*enzymology/pathology
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/analogs & derivatives/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Xenograft Model Antitumor Assays
EDAT- 2005/11/04 09:00
MHDA- 2005/12/24 09:00
CRDT- 2005/11/04 09:00
PHST- 2005/11/04 09:00 [pubmed]
PHST- 2005/12/24 09:00 [medline]
PHST- 2005/11/04 09:00 [entrez]
AID - 65/21/9953 [pii]
AID - 10.1158/0008-5472.CAN-05-0921 [doi]
PST - ppublish
SO  - Cancer Res. 2005 Nov 1;65(21):9953-61. doi: 10.1158/0008-5472.CAN-05-0921.