Growth Stimulation Versus Induction of Cell Quiescence by Hydrogen Peroxide in Prostate Tumor Spheroids Is Encoded by the Duration of the Ca2+ 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 μm) spheroids with 200 μm hydrogen peroxide (H2O2) 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 μm H2O2 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 Ca2+ influx underlined the differential effects of H2O2. Incubation with 200 μmH2O2 released [Ca2+] i from intracellular stores followed by prolonged Ca2+influx. Inhibition of influx by Ca2+-free media or Ni2+, La3+, Mn2+ and SKF-96365 prevented the induction of quiescence and stimulated spheroid growth. Consequently, treatment with 200 μmH2O2 in Ca2+-free media down-regulated p27 kip1 and increased Fos protein. ATP exerted effects comparably to those observed with H2O2. Encoding growth stimulation by [Ca2+] i release and induction of cell quiescence by prolonged Ca2+ influx may provide a general mechanism for the control of tumor growth.

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