Growth stimulation versus induction of cell quiescence by hydrogen peroxide in prostate tumor spheroids is encoded by the duration of the Ca(2+) response.
With increasing size, multicellular prostate tumor spheroids develop regions of quiescent, multidrug-resistant cells expressing the cyclin-dependent kinase inhibitor p27(kip1). Treatment of small (diameter 60 +/- 20 micrometer) spheroids with 200 microM hydrogen peroxide (H(2)O(2)) resulted in cell cycle arrest owing to up-regulation of p27(kip1) and down-regulation of the transcription factor c-Fos. Incubation with 100 nM-1 microM H(2)O(2) led to up-regulation of c-Fos and enhanced tumor growth. Growth stimulation was inhibited by bisindolylmaleimide I, indicating a role for protein kinase C in the signaling cascade that involved the mitogen-activated protein kinase members MEK1,2, ERK1, -2, and c-Jun N-terminal kinase. Changes in Ca(2+) influx underlined the differential effects of H(2)O(2). Incubation with 200 microM H(2)O(2) released [Ca(2+)](i) from intracellular stores followed by prolonged Ca(2+) influx. Inhibition of influx by Ca(2+)-free media or Ni(2+), La(3+), Mn(2+) and SKF-96365 prevented the induction of quiescence and stimulated spheroid growth. Consequently, treatment with 200 microM H(2)O(2) in Ca(2+)-free media down-regulated p27(kip1) and increased Fos protein. ATP exerted effects comparably to those observed with H(2)O(2). Encoding growth stimulation by [Ca(2+)](i) release and induction of cell quiescence by prolonged Ca(2+) influx may provide a general mechanism for the control of tumor growth.
Wartenberg
M
M
Department of Neurophysiology, University of Cologne, D-50931 Cologne, Germany.
Diedershagen
H
H
Hescheler
J
J
Sauer
H
H
D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016762:Genes, fos; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D016760:Proto-Oncogene Proteins c-fos; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006861:Hydrogen Peroxide; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases