Modulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by cell cycle inhibitors.
The effects of cell cycle inhibition on the expression of the multidrug resistance transporter P-glycoprotein (P-gp) as well as of the cyclin-dependent kinase (CDK) inhibitors p27(Kip1) and p21(WAF-1) were investigated in DU-145 prostate tumor spheroids. With increasing spheroid size the number of cells in the G0/G1 phase augmented, whereas the number of cells in the G2/M phase and the S phase of the cell cycle declined. The number of G0/G1 cells was elevated after incubation with either mimosine, staurosporine or serum-free medium. Mitomycin C and roscovitine increased the number of S phase cells. Roscovitine additionally increased cells in the G2/M phase. Incubation in serum-free medium upregulated p21(WAF-1), p27(Kip1) and P-gp. Mimosine treatment resulted in upregulation of p27(Kip1) and P-gp, whereas p21(WAF-1) remained unchanged. Upon roscovitine treatment p27(Kip1) and p21(WAF-1) were downregulated, whereas P-gp was unaltered. Mitomycin C treatment resulted in downregulation of p27(Kip1) and p21(WAF-1); no significant change in P-gp levels was observed. Staurosporine induced upregulation of p21(WAF-1) whereas p27(Kip1) remained unaltered. P-gp was downregulated upon staurosporine treatment, which was owing to an elevation of intracellular reactive oxygen species by this compound. It is concluded that upregulation of P-gp in G0/G1 phase cells requires coexpression of the CDK inhibitor p27(Kip1) but not the CDK inhibitor p21(WAF-1).
Wartenberg
Maria
M
Department of Neurophysiology, University of Cologne, Robert-Koch-Strasse 39, D-50931 Cologne, Germany.
Fischer
Kerstin
K
Hescheler
Jürgen
J
Sauer
Heinrich
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D008898:Mimosine / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D019311:Staurosporine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D011687:Purines; D025521:Tumor Suppressor Proteins; D000077546:Roscovitine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008898:Mimosine; D016685:Mitomycin; D018844:Cyclin-Dependent Kinases; D019311:Staurosporine