Cyclic AMP induces transforming growth factor beta 2 gene expression and growth arrest in the human androgen-independent prostate carcinoma cell line PC-3.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 89 ·No. 8 ·1992-04-15 ·Pages 3556-60

Bang YJ, Kim SJ, Danielpour D, O'Reilly MA, Kim KY, Myers CE, Trepel JB

Abstract

The standard therapy for advanced prostate cancer is androgen ablation. Despite transitory responses, hormonally treated patients ultimately relapse with androgen-independent disease that is resistant to further hormonal manipulation and cytotoxic chemotherapy. To develop an additional approach to the treatment of advanced prostate cancer, we have been studying the signal transductions controlling the growth of human androgen-independent prostate carcinoma cell lines. We report here that elevation of intracellular cAMP markedly inhibits the growth of the hormone-refractory cell line PC-3. To examine the mechanism of cAMP action in PC-3 cells, we tested the effect of the cAMP analog dibutyryl cAMP (Bt2-cAMP) on the regulation of the potent negative growth factor transforming growth factor beta (TGF-beta). Bt2-cAMP selectively induced the secretion of TGF-beta 2 and not TGF-beta 1 by PC-3 cells. This TGF-beta 2 was shown to be bioactive by using the CCL-64 mink lung cell assay. TGF-beta 1 was not activated despite being present at 3-fold higher concentrations than TGF-beta 2. Northern analysis showed that Bt2-cAMP induced an increase in the five characteristic TGF-beta 2 transcripts and had no effect on the level of TGF-beta 1 or TGF-beta 3 transcripts. TGF-beta 2 induction was only weakly enhanced by cycloheximide and was completely inhibited by actinomycin D. These data show that Bt2-cAMP induces the expression of active TGF-beta 2 by PC-3 prostate carcinoma cells, suggesting a new approach to the treatment of prostate cancer and a new molecular mechanism of cAMP action.

MeSH Terms

1-Methyl-3-isobutylxanthine/pharmacology Aprotinin/pharmacology Blotting, Northern Bucladesine/pharmacology Cell Division/drug effects Cell Line Cyclic AMP/analogs & derivatives,pharmacology,physiology Cycloheximide/pharmacology DNA Replication/drug effects Dactinomycin/pharmacology Gene Expression Regulation, Neoplastic/drug effects Humans Kinetics Leupeptins/pharmacology Male Pentoxifylline/pharmacology Phenylmethylsulfonyl Fluoride/pharmacology Prostatic Neoplasms RNA, Neoplasm/genetics,isolation & purification Theophylline/pharmacology Transcription, Genetic/drug effects Transforming Growth Factor beta/biosynthesis,genetics,isolation & purification,pharmacology Tumor Cells, Cultured

Chemicals

Leupeptins RNA, Neoplasm Transforming Growth Factor beta Dactinomycin Phenylmethylsulfonyl Fluoride Bucladesine Aprotinin Cycloheximide Theophylline Cyclic AMP leupeptin Pentoxifylline 1-Methyl-3-isobutylxanthine

Authors & Affiliations

7 authors, click to expand affiliations / ORCID

Bang Y J

Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Kim S J

Danielpour D

O'Reilly M A

Kim K Y

Myers C E

Trepel J B

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29 references, click to expand

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Article Info

Journal

Proceedings of the National Academy of Sciences of the United States of America

Abbr.

Proc Natl Acad Sci U S A

ISSN

0027-8424

DOI

10.1073/pnas.89.8.3556

Published

1992-04-15

Pages

3556-60

Language

English

Region

United States

NLM ID

7505876

PMCID

PMC48907

Subset

External Links

PubMed source DOI: 10.1073/pnas.89.8.3556 PMC Full Text View journal details

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Cyclic AMP induces transforming growth factor beta 2 gene expression and growth arrest in the human androgen-independent prostate carcinoma cell line PC-3.

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