sirolimus and Neoplasms--Squamous-Cell

To investigate the expressions of serine-threonine kinase (Akt)/mammalian target of rapamycin (mTOR)/p70 S6K in oral squamous cell carcinoma (OSCC) and provide references for early diagnosis and prognosis evalua- tion of OSCC.. A total of 51 cases of OSCC, 10 cases of paracancerous mucosa, and 10 cases of normal oral mucosa were collected. The expressions of Akt/mTOR/p70 S6K in these cases were detected using the SP method of immunohisto- chemistry. The correlation between their expressions in OSCC was also analyzed.. The positive expressions ofp-Akt, p-mTOR, and p70 S6K in OSCC were significantly higher than those in normal oral mucosa and paracancerous mucosa. The expressions of p-Akt, p-mTOR, and p70 S6K in OSCC were not correlated with age, gender, and clinical stage; by comparison, these expressions were correlated with lymph node metastasis and pathological grade. Strong positive correlations were also observed between the expressions ofp-Akt, p-mTOR, and p70 S6K in OSCC.. Akt/mTOR/p70 S6K signaling molecules exhibit active expressions in OSCC and may be implicated in the occurrence and development of OSCC.

Topics: Aged; Animals; Humans; Mouth Neoplasms; Neoplasms, Squamous Cell; Phosphorylation; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Head and neck squamous cell carcinoma (HNSCC) has a relatively high mortality rate and poor prognosis. Recently, we showed that overexpression of phosphorylated (p) nuclear factor-kappaB (NF-kappaB) in squamous cell carcinoma of the tonsil (SCCT) and high grade dysplasia is associated with a poor prognosis. Because the mammalian target of the rapamycin (mTOR) pathway contributes to the activation of NF-kappaB through immunophilin/mTOR signaling, we investigated: (a) the immunohistochemical expression and state of activation and potential clinical significance of components of the mTOR signal transduction pathway in SCCT patients (morphoproteomics); and (b) the inhibitory effects of rapamycin on the growth and state of activation of mTOR in 2 HNSCC cell lines (pharmacoproteomics). Archival biopsy materials from 39 patients with SCCT were studied by immunohistochemistry for the expression of p-mTOR (Ser 2448), and p-p70S6K (Thr 389), and/or cyclin D1. Results for SCCT were compared with adjacent non-neoplastic epithelium, when present, and with normal tonsillar epithelium from approximately age-matched controls; clinical outcomes were also assessed. SCCT showed mTOR (Ser 2448) expression in 93% (30/32 cases) with 2+ or 3+ plasmalemmal and/or cytoplasmic intensity in 84% vs 42% in surface epithelium from normal tonsils (p <0.001). The mean combined expression score (signal intensity x percentage of positive cells) for p-p70S6K was significantly greater in the SCCT group vs adjacent non-neoplastic squamous epithelium and normal tonsillar epithelium of the control group (p <0.05). A relationship existed between higher p-p70S6K expression levels in the non-neoplastic squamous epithelium adjacent to the SCCT and increased risk of death from disease (hazard ratio = 7.9; 95% confidence interval (CI) = 2.1 to 29.9; p = 0.002). There was also a relationship between nuclear expression of cyclin D1 in SCCT and shortened recurrence-free survival (p = 0.015). Two human HNSCC cell lines, SCC-15 and FaDu, were incubated with and without rapamycin to assess its impact on growth and on the expression of p-mTOR. Rapamycin in a dose-dependent fashion inhibited growth more in SCC-15, which correlated with a greater reduction in constitutively activated p-mTOR (Ser 2448) as shown by Western blotting. In conclusion, these morphoproteomic and pharmacoproteomic data collectively provide a rationale for selecting mTOR effectors as therapeutic targets in HNSCC.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cyclin D1; Humans; Immunohistochemistry; Neoplasms, Squamous Cell; Protein Kinases; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Tonsillar Neoplasms; TOR Serine-Threonine Kinases