Inducible P27Kip1 expression inhibits proliferation of K562 cells and protects against apoptosis induction by proteasome inhibitors

Overexpression of the cyclin-dependent kinase inhibitor P27(Kip1) has been demonstrated to induce cell cycle arrest and apoptosis in various cancer cell lines, but has also been associated with the opposite effect of enhanced survival of tumor cells and increased resistance towards chemotherapeutic treatment. To address the question of how p27(KIP1) expression is related to apoptosis induction, we studied doxycycline-regulated p27(KiP1) expression in K562 erythroleukemia cells. p27(KiP1) expression effectively retards proliferation, but it is not sufficient to induce apoptosis in K562 cells. p27(Kip1)-expressing K562 cells, however, become resistant to apoptosis induction by the proteasome inhibitors PSI, MG132 and epoxomicin, in contrast to wild-type K562 cells that are efficiently killed. Cell cycle arrest in the S phase by aphidicolin, which is not associated with an accumulation. of p27(Kip1) protein, did not protect K562 cells against the cytotoxic effect of the proteasome inhibitor PSI. The expression levels of p27(Kip1) thus constitute an important parameter, which decides on the overall sensitivity of cells against the cytotoxic effect of proteasome inhibitors.