PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways

The tumour suppressor PTEN inhibits cell growth through multiple mechanisms . We have previously demonstrated that overexpression of PTEN in MCF-7 brea st cancer cells causes G(1) arrest followed by cell death, the latter of wh ich is believed to be mediated by the phosphoinositol-3-kinase (PI3K) and A kt/PKB pro-apoptotic pathways. In this present study, we show that culture in the presence of low levels of growth factors increased PTEN-mediated gro wth suppression through the enhancement of PTEN-induced cell death. The cas pase 9-specific inhibitor, ZVAD, blocked PTEN-induced cell death without al tering the effect of PTEN on cell cycle distribution. Depending on the leve l of expression, overexpression of dominant-negative Akt induces more cell death and has less effect on the cell cycle or induces similar or decreased cell death without affecting the cell cycle compared with effects on cell death and the cell cycle when overexpressing PTEN, These observations in su m suggest that, in MCF-7 breast cancer cells, the apoptotic cells induced b y the overexpression of PTEN did not derive from the G,arrested cells. Furt her, the effect of PTEN on cell death is mediated through the PI3K/Akt path way whereas PTEN-mediated cell cycle arrests are through PI3K/Akt-dependent and -independent pathways.