p27^Kip1 is inactivated in human colorectal cancer by cytoplasmic localization associated with activation of Akt/PKB

p27^Kip1 is a nuclear member of the Kip/Cip family of cyclin-dependent kinase inhibitors and is a negative cell cycle regulator that is thought to play a role in tumour suppression. Reduced levels of p27^Kip1 are frequent in human cancers and these have been associated with poor prognosis. We have analysed p27^Kip1 expression and intracellular localization in 70 human colorectal cancers by Western blotting and immunohistochemistry and the results related to Akt expression and clinical pathological parameters. p27^Kip1 protein expression, as evaluated by Western blotting, was absent or reduced in about 63% of colorectal cancers compared with both peritumoral and normal tissue. Cytoplasmic p27^Kip1 was detected, by immunohistochemical analysis, in 30% (21 of 70) of cases indicating that translocation of p27^Kip1 protein into the cytoplasm may be responsible for p27^Kip1 inactivation. The analysis of phosphorylated Akt by Western blotting indicated that it was expressed in 38% (8 of 21) of tumours showing cytoplasmic p27^Kip1. Patients whose cancer presented accumulation of cytoplasmic p27^Kip1 showed poorer outcomes for cancer-related relapse and survival. These results suggest that cytoplasmic p27^Kip1 localization, associated or not with Akt activation, may contribute to colorectal tumorigenesis and metastasis and it may be useful as a negative prognostic factor for the outcome of patients with colorectal cancer.