Prospective studies and recent intervention trials suggest that the risk of some
cancers, including respiratory tract
cancers, may be inversely related to
selenium (SE) intake, and this is supported by strong experimental evidence with chemical-induced animal
cancer models. How this
cancer-protective effect is mediated is unclear, but interference with the balance of growth/apoptosis during
tumor outgrowth is one plausible hypothesis. In general, there is a correlation between the effectiveness of SE compounds as chemopreventive agents in vivo and their ability to inhibit cell growth and induce apoptosis in vitro. This study has investigated the signal transduction pathways affected by SE compounds in biopsies of normal human oral mucosa cells and human oral
squamous carcinoma cells (SCCs), using a primary culture system. Two SE compounds were tested:
selenodiglutathione (SDG), the primary metabolite of
selenite and the most commonly used
cancer-protective SE compound in animal models, and the synthetic SE compound,
1,4-phenylenebis(methylene)selenocyanate (p-XSC), one of the most potent chemopreventive pharmacological SE compounds. Three novel findings are reported: (a) SCCs were found to be significantly more sensitive to induction of apo ptosis by SDG than normal human oral mucosa cells, though the differences were marginal with p-XSC; (b) both SE compounds induced the expression of
Fas ligand (Fas-L) in oral cells to a degree that correlated with the extent of apoptosis induction; and (c) both SDG and p-XSC induced the stress pathway
kinases, Jun NH2-terminal
kinase (JNK) and p38
kinase, at concentrations causing apoptosis; p-XSC, and to a lesser extent SDG, also activated extracellular regulated
kinases 1&2 (ERKs 1&2) and
protein kinase-B or Akt. To test their functional involvement, the effect of inhibiting each of these pathways on induction of apoptosis by SDG and p-XSC was determined in SCCs. Inhibiting the ERKs 1&2 or Akt pathways with specific chemical inhibitors (
PD98059 or
LY294002, respectively) did not affect the extent of apoptosis induced by SDG or p-XSC (with the exception of
LY294002, which actually enhanced the level of induction of apoptosis by SDG). The JNK pathway appeared to be most important for induction of Fas-L and apoptosis because concentrations of
SB202190 that inhibited activation of both the JNK and p38
kinase (but not ERKs 1&2) in SCC reduced the extent of induction of Fas-L and apoptosis by SDG and p-XSC, whereas lower concentrations that inhibited activation only of p38
kinase did not. This was confirmed by the fact that exogenous expression of a dominant negative deletion mutant of c-Jun (TAM67) reduced the induction of both apoptosis and Fas-L by SDG.