One of the key drivers for the mitogenesis of oral squamous cell carcinoma (OSCC) cells is activation of the epidermal growth factor receptor (EGFR) by ligands such as epidermal growth factor (EGF) and transforming growth factor-a (TGF-a). However, the mechanism by which activated EGFR mediates OSCC cell mitogenesis is still unclear. Recent studies indicate that in neuronal cells never growth factor (NGF) stimulates phospholipase C-?1 (PLC-?1) translocation to the nucleus. The nuclear PLC-?1 acts as a guanine nucleotide exchange factor and activates the short form of phosphatidylinositol 3-OH kinase enhancer (PIKE-S) in the nucleus through its SH3 domain. The activated PIKE-S then stimulates nuclear phosphatidylinositol 3-OH kinase (PI3K) activity essential for cell mitogenesis. Our preliminary results show that PIKE-S is present in an OSCC cell line (SCC4 cells). EGF induces PLC-?1 translocation to the nucleus where it binds to the nuclear PIKE-S. PLC-?1 and PIKE-S are required for EGF-induced SCC4 cell mitogenesis. These data suggest a novel pathway for EGFR ligand-induced SCC4 cell mitogenesis. Our HYPOTHESIS is that nuclear PIKE-S activated by the SH3 domain of PLC-?1 is required for EGFR ligand-induced OSCC cell mitogenesis. EGFR ligand (EGF or TGF-a) stimulates nuclear PIKE-S through the SH3 domain of nuclear PLC-?1 and enhances nuclear PI3K activity. Phosphatidylinositol 3,4,5-triphosphate (PIP3) produced in the nucleus by PI3K attracts protein kinase C-? (PKC-?) to the nucleus to phosphorylate nucleolin, an RNA binding protein required for DNA synthesis.
SPECIFIC AIMS : (1) Determine the cellular localization of PLC-?1, PIKE-S, PI3Ks and PKC-? in OSCC cells in response to EGF and TGF-a. (2) Determine whether PIKE-S interacts with PLC-?1 and PI3Ks, and whether knocking down PLC-?1 or overexpression of PLC-?1 in OSCC cells affects EGF- and TGF-a-induced nuclear PIKE-S, PI3Ks and PKC-? activation, nuclear nucleolin phosphorylation, OSCC cell mitogenesis, survival and invasion. (3) Determine the role of PIKE-S in mediating EGF- and TGF-a-induced nuclear PI3Ks and PKC-? activation, nuclear nucleolin phosphorylation, OSCC cell mitogenesis, survival and invasion. SIGNIFICANCE: These studies will uncover a novel pathway for EGF ligand induced OSCC mitogenesis and may provide therapeutic targets for OSCC. ? ? Narrative: Oral squamous cell carcinoma is the sixth most common type of carcinoma worldwide and the mechanism of uncontrolled tumor growth is unclear. These studies will provide insight into the mechanism important for epidermal growth factor induced oral squamous cell carcinoma growth. Understanding these mechanisms will bring the possibility of new molecular targets for development novel therapeutic options for the control of oral squamous cell carcinoma. ? ? ?
