Abstract
Both cAMP and retinoids play a role in cell differentiation and the control of cell growth. A site-selective cAMP analog, 8-Cl-cAMP and retinoic acid synergistically inhibit growth and induce apoptosis in certain cancer cells. In advanced or recurrent malignant diseases, retinoic acid (RA) is not effective even at doses that are toxic to the host. The objective of our present study was to examine the mechanism(s) of synergistic effects of retinoic acid (9-cis, 13-cis or all-trans RA) and 8-Cl-cAMP on apoptosis in human ovarian cancer NIH: OVCAR-3 and OVCAR-8 cells. RA induced growth inhibition and apoptosis in OVCAR-3 and OVCAR-8 cells. 8-Cl-cAMP acted synergistically with RA in inducing and activating retinoic acid receptor β (RARβ) which correlates with growth inhibition and apoptosis in both cell types. In addition, induction of apoptosis by RA plus 8-Cl-cAMP requires caspase-3 activation followed by cleavage of anti-poly(ADP-ribose) polymerase. Furthermore, mutations in CRE-related motif within the RARβ promoter resulted in loss of both transcriptional activation of RARβ and synergy between RA and 8-Cl-cAMP. RARβ expression appears to be associated with induction of apoptosis. Introduction of the RARβ gene into OVCAR-3 cells resulted in gain of RA sensitivity. Loss of RARβ expression, therefore, may contribute to the tumorigenicity of human ovarian cancer cells. Thus, combined treatment with RA and 8-Cl-cAMP may provide an effective means for inducing RARβ expression leading to apoptosis in ovarian cancer cells.
Similar content being viewed by others
References
Brooks SC, Kazmer S, Levin AA, Yen A: Myeloid differentiation and retinoblastoma phosphorylation changes in HL-60 cells induced by retinoic acid receptor-and retinoic X receptor-selective retinoic acid analogs. Blood 87: 227-237, 1996
Ong DE, Newcomer ME, Chytil F: Cellular retinoic-binding proteins. In: M.B. Sporn, A.B. Roberts, D.S. Goodman (eds). The Retinoids. Raven Press, New York, 1994, pp 283-317
Hong WK, Itri LM: Retinoids and human cancer. In: M.B. Sporn, A.B. Robert, D.S. Goodman (eds). The Retinoids: Biology, Chemistry and Medicine. Raven Press, New York, 1994, pp 597-630
Spron MB, Roberts AB, Goodman DS: The Retinoids: Biology, Chemistry and Medicine, Ed. 2., Raven Press, New York, 1994
Chambon P: A decade of molecular biology of retinoid acid receptors. FASEB J 10: 940-954, 1996
Ponzoni M, Booca P, Chiesa V, Decensi A: Differentiation effects of N-(4-(hydroxyphenyl)retinamide and retinoic acid on neuroblastoma cells: Apoptosis vs. differentiation. Cancer Res 55: 853-861, 1995
Hoffmann B, Lehmann JM, Zhang XK, Hermann T, Husmann M, Graupner G, Pfahl M: A retinoic acid receptor-specific element controls the retinoic acid receptor-β promoter. Mol Endocrinol 4: 1727-1736
Liu Y, Lee M, Wang H-G, Li Y, Hashimoto Y, Klaus M, Reed JC, Zhang X-K: Retinoic acid receptor β mediates the growth inhibitory effect of retinoic acid by promoting apoptosis in human breast cancer cells. Mol Cell Biol 16: 1138-1149, 1996
Seewaldt VL, Johnson BS, Parker MB, Collins SJ, Swisshelm K: Expression of retinoic acid receptor β mediates retinoic acid-induced growth arrest and apoptosis in breast cancer cells. Cell Growth Diff 6: 1077-1088, 1995
Caliaro M, Marmouget C, Guichard S, Mazars Ph, Valette A, Moisand A, Bugat R, Jozan S: Response of four human ovarian carcinoma cell lines to all-trans retinoic acid: relationship with induction of differentiation and retinoic acid receptor expression. Int J Cancer 56: 743-748, 1994
Chao W.-R, Hobbs PD, Jong L, Zhang X-K, Zheng Y, Wu Q, Shroot B, Dawson MI: Effects of receptor class-and subtypeselective retinoids and an apoptosis-inducing retinoid on the adherent growth of the NIH: OVCAR-3 ovarian cancer cell line in culture. Cancer Res 115: 1-7, 1997
Wu S, Donigan A, Platsoucas CD, Jung W, Soprano DR, Soprano KJ: All-trans retinoic acid blocks cell cycle progression of human ovarian adenocarcinoma cells at late G1. Exp Cell Res 232: 277-286, 1997
Wu S, Zhang Z-P, Zhang D, Soprano DR, Soprano KJ: Reduction of both RAR and RXR levels is required to maximally alter sensitivity of CA-OV3 ovarian tumor cells to growth suppression by all-trans retinoic acid. Exp Cell Res 237: 118-126, 1997
Krebs EG, Beavo JA: Phosphorylation-dephosphorylation of enzymes. Annu Rev Biochem 88: 923-939, 1979
Cho-Chung YS, Nesterova M, Kondrashin A, Noguchi K, Srivastava RK, Pepe S: Antisense-protein kinase A: A single-genebased therapeutic approach. Antisense Nucl Acid Drug Dev 7: 217-223, 1997
Lanotte M, Riviere JB, Hermouet S, Houge G, Wintermyr OK, Gjertsen BT, Doskeland SO: Programmed cell death (apoptosis) is induced rapidly and with positive co-operativity by activation of cyclic adenosine monophosphate-kinase I in a myeloid leukemia cell line. J Cell Physiol 146: 73-80, 1991
Vintermyr OK, Gjersten BT, Lanotte M, Doskeland SO: Microinjected catalytic subunit of cAMP-dependent protein kinase induces apoptosis in myeloid leukemia IPC-8U cells. Exp Cell Res 206: 157-161, 1993
Fontana JA: Interaction of retinoids and tamoxifen on the inhibition of human mammary carcinoma cell proliferation. Exp Cell Biol 55: 136-144, 1987
Koga M, Sutherland RL: Retinoic acid acts synergistically with 1,25-dihydroxyvitamin D3 or antiestrogen to inhibit human breast cancer cell proliferation. J Steroid Biochem Mol Biol 39: 455-460, 1991
Widschwendter M, Daxenbichler G, Dapunt O, March C: Effects of retinoic acid and gamma-interferone on expression of retinoic acid receptor and cellular retinoic acid-binding protein in breast cancer cells. Cancer Res 55: 2135-2139, 1995
Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herlich P, Karin M: Phorbol ester-inducible genes contain a common cis element recognizxed by a TPA-modulated trans-acting factor. Cell 49: 729-739, 1987
Foulkes NS, Borrelli E, Sassone-Corsi P: CREM gene: Use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription. Cell 64: 739-749, 1991
Martin SJ, Green DR: Protease activation during apoptosis. Death by a thousand cuts? Cell 82: 349-352, 1995
Kruyt FA, Golkers G, van den Brink CE, van der Saag PT: A cyclic AMP response element is involved in retinoic acid-dependent RARβ2 promoter activation. Nucl Acid Res 20: 6393-6399, 1992
Tortora G, Ciadiello F, Pepe S, Tagliaferri P, Ruggiero A, Bianco C, Guarrasi R, Miki K, Bianco AR: Phase I clinical study with 8-chlorocAMP and evaluation of immunological effects in cancer patients. Clin Can Res 1: 377-384, 1995
Sabichi AL, Hendricks DT, Bober MA, Birrer MJ: Retinoic acid receptor β expression and growth inhibition of gynecological cancer cells by the synthetic retinoid N-(4-hydroxyphenyl) retinamide. J. Natl Cancer Inst 90: 597-605, 1998
Henkart PA: ICE family proteases: Mediators of all apoptotic cell death? Immunity 4: 195-201, 1996
Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG: Specific proteolytic cleavage of poly(ADP-ribose)polymerase an early marker of chemotherapy-induced apoptosis. Cancer Res 53: 3976-3985, 1993
Houle B, Ledue F, Bradley WEC: Implication of RARb in epidermoid (squamous) carcinoma cells. Exp Cell Res 195: 163-170, 1993
Xu, X-C, Sozzi G, Lee LS, Lee JJ, Pastorino U, Pilotti S, Kurie LM, Hong WK, Lotan R: Suppression of retinoic acid receptor β in non-small cell lung cancer in vivo:_Implications for lung cancer development. J Natl Cancer Inst 89: 624-629
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Srivastava, R.K., Srivastava, A.R. & Cho-Chung, Y.S. Synergistic effects of 8-Cl-cAMP and retinoic acids in the inhibition of growth and induction of apoptosis in ovarian cancer cells: Induction of retinoic acid receptor β. Mol Cell Biochem 204, 1–9 (2000). https://doi.org/10.1023/A:1007074814676
Issue Date:
DOI: https://doi.org/10.1023/A:1007074814676