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Augmentation of Postconfluence Growth Arrest of 10T Fibroblasts by Endogenous Cyclic Adenosine 3':5'-Monophosphate¹

Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813

We have previously demonstrated that, by elevating intraceliular adenosine 3':5'-cyclic monophosphate (cAMP) levels by inhibition of cAMP phosphodiesterase with Ro 20-1724 or by forskolin stimulation of adenylcyclase, the growth of neoplastically transformed 10T fibroblasts could be inhibited when these cells were in contact with growth-inhibited nontransformed 10T cells (J. S. Bertram and M. B. Faletto, Cancer Res., 45: 1946–1952, 1985) and furthermore that the extent of this growth inhibition correlated strongly with the degree of junctional communication between the two cell types (P. P. Mehta et al., Cell, 44: 187–196, 1986). To determine if these treatments enhance the degree of growth control of the nontransformed 10T cells, cultures were exposed to varying concentrations of Ro 20–1724 and/or forskolin. Drug treatment caused no significant effects on growth rate or cell spreading when cells were treated during logarithmic growth phase; however, major reductions of up to 70% in confluent saturation density and concomitant increases in cell spreading occurred in cultures making extensive cell/cell contacts. Decreases in saturation density correlated strongly with induced elevations of both intra- and extracellular cAMP concentrations. These effects could not be duplicated by the addition of exogenous cAMP agonists 8-bromo-cAMP and/or dibutyryl-cAMP. Two-dimensional electrophoresis of phosphate-labeled proteins revealed that forskolin treatment induced a quantitatively and qualitatively different phosphorylation profile than did 8-bromo-cAMP. Both basal and drug-induced intracellular cAMP levels fell as cells progressed from logarithmic to confluent growth state, implying that cells become sensitized to cAMP by the attainment of extensive cell/cell contacts. It is suggested that the drug-induced elevations of endogenously synthesized cAMP are accentuating a physiological role of cAMP on the postconfluent growth arrest of murine fibroblasts. The requirements for cell/cell contact and the known increased junctional communication induced by cAMP furthermore suggest that cAMP is enhancing the junctional transfer of a growth-inhibiting regulatory molecule. A likely candidate is cAMP itself.

¹ Supported by Grant CA 39604 from the US National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 7/14/87. Revised 12/16/87. Accepted 12/31/87.

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