Inducible p27(Kip1) 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.
Drexler
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Max Planck Institute for Physiological and Clinical Research, Department of Molecular Cell Biology, Bad Nauheim, Germany. h.drexler@kerckhoff.mpg.de
Pebler
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D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D016590:Aphidicolin / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000502:physiology*; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D005822:Genetic Vectors; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D007976:Leupeptins / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D012190:Retroviridae / Q000235:genetics; D016196:S Phase / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000502:physiology*
D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D006454:Hemoglobins; D007976:Leupeptins; D009097:Multienzyme Complexes; D009842:Oligopeptides; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016590:Aphidicolin; D004317:Doxorubicin; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C078846:epoxomicin