RT Journal Article
SR Electronic
T1 Persistent Activation of the Akt Pathway in Head and Neck Squamous Cell Carcinoma
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 4029
OP 4037
DO 10.1158/1078-0432.CCR-03-0249
VO 10
IS 12
A1 Amornphimoltham, Panomwat
A1 Sriuranpong, Virote
A1 Patel, Vyomesh
A1 Benavides, Fernando
A1 Conti, Claudio J.
A1 Sauk, John
A1 Sausville, Edward A.
A1 Molinolo, Alfredo A.
A1 Gutkind, J. Silvio
YR 2004
UL http://clincancerres.aacrjournals.org/content/10/12/4029.abstract
AB Squamous carcinomas of the head and neck (HNSCC) represent the sixth most common cancer among men worldwide and a major cause of morbidity and mortality due to its relatively poor prognosis. As part of ongoing studies addressing the molecular events underlying tumor progression in HNSCC, we have explored the nature of the proliferative pathways in which dysregulation may promote aberrant cell growth in this tumor type. The serine/threonine protein kinase Akt is a downstream target of phosphatidylinositol 3-kinase and a key regulator of normal and cancerous growth and cell fate decisions. Therefore, in this study, we have examined the status of activation of Akt in different stages of squamous cell carcinoma development in mice and in clinical samples from HNSCC patients. By immunohistochemical analysis, using a recently developed phosphorylation state-specific antibody, we demonstrated that Akt activation correlates closely with the progression of mouse skin squamous cell carcinoma. We also observed that activation of Akt is a frequent event in human HNSCC because active Akt can be detected in these tumors with a pattern of expression and localization correlating with the progression of the lesions. In line with these observations, Akt was constitutively activated in a large fraction of HNSCC-derived cell lines. We also provide evidence that the Akt signaling pathway may represent a biologically relevant target for a novel antineoplastic agent, UCN-01, which recently has been shown to be active in cellular and xenograft models for HNSCC at concentrations safely achievable in clinically relevant situations.