Abstract
BackgroundWe reported increased levels of Phosphatidyl Inositol synthase (PI synthase), (enzyme that catalyses phosphatidyl inositol (PI) synthesis-implicated in intracellular signaling and regulation of cell growth) in smokeless tobacco (ST) exposed oral cell cultures by differential display. This study determined the clinical significance of PI synthase overexpression in oral squamous cell carcinoma (OSCC) and premalignant lesions (leukoplakia), and identified the downstream signaling proteins in PI synthase pathway that are perturbed by smokeless tobacco (ST) exposure.MethodsTissue microarray (TMA) Immunohistochemistry, Western blotting, Confocal laser scan microscopy, RT-PCR were performed to define the expression of PI synthase in clinical samples and in oral cell culture systems.ResultsSignificant increase in PI synthase immunoreactivity was observed in premalignant lesions and OSCCs as compared to oral normal tissues (p = 0.000). Further, PI synthase expression was significantly associated with de-differentiation of OSCCs, (p = 0.005) and tobacco consumption (p = 0.03, OR = 9.0). Exposure of oral cell systems to smokeless tobacco (ST) in vitro confirmed increase in PI synthase, Phosphatidylinositol 3-kinase (PI3K) and cyclin D1 levels.ConclusionCollectively, increased PI synthase expression was found to be an early event in oral cancer and a target for smokeless tobacco.
Highlights
We reported increased levels of Phosphatidyl Inositol synthase (PI synthase), (enzyme that catalyses phosphatidyl inositol (PI) synthesis-implicated in intracellular signaling and regulation of cell growth) in smokeless tobacco (ST) exposed oral cell cultures by differential display
To determine the biological significance of PI Synthase, we investigated the effect of ST on induction of this enzyme using oral cancer cell lines and oral epithelial cell cultures [19]
Smokeless Tobacco activates PI Synthase in oral epithelial cell cultures To determine the optimal dose and duration for ST treatment, a human oral lesion (AMOL) and HSC-2 cells were treated with different concentrations of ST ranging from 1 μg/ml to 1000 μg/ml for varying time periods ranging from 4 h to 120 h
Summary
We reported increased levels of Phosphatidyl Inositol synthase (PI synthase), (enzyme that catalyses phosphatidyl inositol (PI) synthesis-implicated in intracellular signaling and regulation of cell growth) in smokeless tobacco (ST) exposed oral cell cultures by differential display. Epidemiological evidence shows a correlation between use of smokeless tobacco (ST) and lesions of the oral cavity as Intense efforts are being directed towards developing accurate predictors of clinical outcome using high throughput techniques such as differential displayreverse transcription PCR (DD), cDNA microarrays and proteomics to assess global gene/protein expression patterns in head and neck cancer [12,13,14,15] In search of such novel molecular targets, our laboratory reported increased levels of phosphatidyl inositol synthase (PI Synthase) or CDP-diacylglycerol-inositol 3-phosphatidyl transferase (CDIPT) transcripts in cell cultures from a human oral lesion (AMOL), exposed to ST extracts using DD [16], providing the rationale for in-depth investigation of biological and clinical significance of its expression in oral cancer.
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