Differential modulation of zinc-stimulated p21^Cip/WAF1 and cyclin D1 induction by inhibition of PI3 kinase in HT-29 colorectal cancer cells

Activation of the extra cellular signal regulated kinase (ERK) pathway is involved in both proliferation and growth arrest of cells depending on intensity and duration of stimuli. In this study, we have elucidated differential regulation of the zinc-stimulated p21^Cip/WAF1 and cyclin D1 activation by inhibition of phosphoinositide 3-kinase (PI3K). In HT-29 colorectal cancer cells, the ERK activities were increased by zinc, which was accompanied by the induction of p21^Cip/WAF1 and cyclin D1. However, in the HT-29 cells pre-treated with PI3K inhibitor, LY294002, zinc induced further the p21^Cip/WAF1 induction whereas abrogated cyclin D1 induction. In addition, the induction of p21^Cip/WAF1 expression completely inhibited the incorporation of bromodeoxyuridine (BrdU) into the nucleus, indicating that p21^Cip/WAF1 is an important indicator for ERK-dependent growth arrest. These studies suggest presence of an inter-related regulatory mechanism of cell proliferation by ERK and PI3K pathways.