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Differential Effects of Dibutyryl Cyclic Adenosine Monophosphate and Retinoic Acid on the Growth, Differentiation, and Cyclic Adenosine Monophosphate-binding Protein of Murine Neuroblastoma Cells¹

Laboratories of Cyclic Nucleotide Research, Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas 77225 [N. P.]; and the Department of Tumor Biology, The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Texas 77030 [D. L., R. L.].

Dibutyryl cyclic adenosine 3':5'-monophosphate (Bt₂cAMP) and ß-all-trans retinoic acid (RA) have been shown separately, and in some cases in combination, to modulate the growth, differentiation, and cAMP-dependent protein kinase (PK-A) activity of various tumor cells. The effects of Bt₂cAMP and RA on a cholinergic clone (S20) of C1300 mouse neuroblastoma cells were explored in the present study. Treatment of these cells with 1 mM Bt₂cAMP for 3 or more days resulted in 93% inhibition of cell proliferation in monolayer cultures and in 98% inhibition of colony formation in semisolid medium (0.5% agarose). In contrast, treatment of the cells with 1 or 10 µM RA had no inhibitory effects on cell proliferation in monolayer cultures but enhanced colony formation in agarose by up to 130%. The growth of cells treated with a combination of Bt₂cAMP and RA was inhibited, although less so than with Bt₂cAMP alone. Cells treated with Bt₂cAMP alone or Bt₂cAMP and RA extended long, neurite-like, cellular processes indicative of differentiation, whereas only a few untreated or RA-treated cells produced such extensions. The amount of [³H]cAMP-binding protein increased gradually up to 2-fold during a 3-day treatment with Bt₂cAMP; in contrast it decreased by nearly 2-fold during RA treatment. These changes occurred in the level of the type I regulatory subunit (RI) of PK-A as determined by photoaffinity labeling with 8-azidoadenosine cyclic 3':5'-[³²P]monophosphate. The increase in RI following Bt₂cAMP treatment was corroborated by DEAE-cellulose chromatography. This analysis also demonstrated that type I PK-A is the predominant kinase in the untreated S20 cells and that RI exists as a free subunit in Bt₂cAMP-treated cells. The activity of PK-A decreased by about 20% following treatment with either Bt₂cAMP or RA and by 45% following treatment with a combination of both agents. These results suggest that the distinct effects of Bt₂cAMP and RA on the anchorage-independent growth of S20 cells may be related to their opposite effects on the level of RI.

¹ Supported in part by M. D. Anderson Annual Campaign Funds.

² To whom requests for reprints should be addressed, at Department of Tumor Biology, Box 108, M. D. Anderson Hospital, University of Texas System Cancer Center, 6723 Bertner Avenue, Houston, TX 77030.

Received 6/25/86. Revised 1/12/86. Revised 2/ 3/87. Accepted 2/ 5/87.

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