Growht Ingibition of Human Ovarian Cancer Cells by Differential Modulation of Protein Kinase A Isozymes

  • Seo, Jin (Department of Molecular Biology, Seoul National University) ;
  • Kim, Se-Nyun (Department of Molecular Biology, Seoul National University) ;
  • Lee, Gap-Ryol (Department of Molecular Biology, Seoul National University) ;
  • Kim, So-Young (Institute of Molecular Biology and Genetics, Seoul National University) ;
  • Park, Sang-Dal (Department of Molecular Biology, Seoul National University) ;
  • Hong, Seung-Hwan (Institute of Molecular Biology and Genetics, Seoul National University)
  • Published : 1997.06.01

Abstract

We examined the effect of modulation of PKA isozymes on the growth of human ovarian cancer cells. Three ovarian cancer cell lines, 2774, SK-OV-3, and OVCAR-3, were examined in this study. The treatment of 5 uM 8-CI-cAMP, which has been known to down-regulate RI (or type 1 PKA) and up-regulate RII (or type II PKA), markedly inhibited the growth of all cell lines (50-80% at day 6). To test whether alteration in PKA regulatory subunits level can change the growth characteristics of ovarian cancer cells, we introduced RIIB- expression construct and Rla antisense-expression construct into 2774 cells. The overexpression of RIIB down-regulated Rla protein, and the antisense-expression of Rla up-regulated RIIB protein, showing that the intracellular levels of RI and RII are reciprocally regulated. In both cases, cell growth was reduced by 30% at day 2. These results indicate that the growth of ovarian cancer cells is controlled by the signals from PKA isozymes, and the modulation of PKA isozymes can be employed for the human ovarian cancer therapy.

Keywords

References

  1. Cancer Res v.48 Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay Alley MC;Scudiero DA;Monks A;Hursey ML;Czerwinski MJ;Fine DL;Abbott BJ;Mayo JG;Shoemaker RH;Boyd MR
  2. Cancer Res v.49 Inhibition of growth and modulation of gene expression in human lung carcinoma in athymic mice by site-selective 8-Cl-cyclic adenosine mono-phosphate Ally S;Clair T;Katsaros D;Tortora G;Yokozaki H;Finch RA;Avery TL;Cho-Chung YS
  3. Proc Natl Acad Sci USA v.85 Selective modulation of protein kinase isozymes by the site-selective analog 8-chloroadenosine 3',5'-cyclic monophosphate provides a biological means for control of human colon cancer cell growth Ally S;Tortora G;Clair T;Grieco D;Merlo G;Katsaros D;Ogreid D;Doskeland SO;Jahnsen T;Cho-Chung YS
  4. Proc Natl Acad Sci USA v.92 Point mutation of the autophosphorylation site or in the nuclear location signal causes protein kinase A Rllβ regulatory subunit to lose its ability to revert transformed fibroblasts Budillon A;Cereseto A;Kondrashin A;Nesterova M;Merlo G;Clair T;Cho-Chung YS
  5. Cancer Res v.50 Role of cyclic AMP receptor proteins in growth, differentiation, and suppression of malignancy: new approaches to therapy Cho-Chung, YS
  6. FEBS Lett v.224 Site-selective cAMP analogs induce nuclear translocation of the Rll cAMP receptor protein in Ha-MuSV-transformed NIH/3T3 cells Clair T;Ally S;Tagliaferri P;Robins RK;Cho-Chung YS
  7. J Biol Chem v.259 Hormonal regulation of cyclic AMP-dependent protein kinase in cultured ovarian granulosa cells Darbon J-M;Knecht M;Ranta T;Dufau ML;Catt KJ
  8. Endocrinology v.97 Ovarian cyclic adenosine monophosphate-dependent protein kinase activity: ontogeny and effect of gonadotropins DeAngelo AB;Schweppe JS;Jungmann JA;Huber P;Eppenberger U
  9. Biochim Biophys Acta v.714 Rat ovarian nuclear protein kinases Hunzicker-Dunn M
  10. FEBS Lett v.223 Site-selective cyclic AMP analogs provide a new approach in the control of cancer cell growth Katsaros D;Tortora G;Tagliaferri P;Clair T;Ally S;Neckers L;Robins RK;Cho-Chung YS
  11. Intl J Oncol v.8 Overexpression of Rllβ regulatory subunit of protein kinase A Induces growth inhibition and reverse-transformation in SK-N-SH human neuroblastoma cells Kim SN;Lee GR;Cho-Chung YS;Park SD;Hong SH
  12. Biochem Biophys Res Commun v.232 Type Ⅱ protein kinase A up-regulation is sufficient to induce growth inhibition in SK-N-SH human neuroblastoma cells Kim SN;Lee GR;Hwang ES;Lee J-H;Park SD;Cho-Chung YS;Hong SH
  13. J Biol Chem v.256 The regulatory role of cyclic AMP in hormone-induced granulosa cell differentiation Knecht M;Amsterdam A;Catt K
  14. Mol Endocrinol v.2 Molecular cloning, complementary deoxyribonucleic acid structure and predicted full-length amino acid sequence of the hormone-inducible regulatory subunit of 3'-5'-cyclic adenosine monophosphate-dependent protein kinase from human testis Levy FO;Oyen O;Sandberg M;Tasken K;Eskild W;Hansson V;Jahnsen T
  15. Oncogene v.4 Infection with a TGF-α retroviral vector transforms normal mouse mammary epithelial cells but not normal rat fibroblasts McGeady ML;Kerby S;Shankar V;Ciardiello F;Salomon DS;Seidman M
  16. Recent Prog Horm Res v.44 Analysis of the cAMP-dependent protein kinase system using molecular genetic approaches McKnight GS;Clegg CH;Uhler MD;Chrivia JC;Cadd GG;Correll LA;Otten AD
  17. FEBS Lett v.254 Site-selective 8-Cl-cAMP which causes growth inhibition and differentiation increases DNA (CRE)-binding activity in cancer cells Mednieks MI;Yokozaki H;Merlo GR;Tortora G;Clair T;Ally S;Tahara E;Cho-Chung YS
  18. Nature Med v.1 A single-injection protein kinase A-directed antisense treatment to inhibit tumour growth Nesterova M;Cho-Chung YS
  19. Eur J Biochem v.235 Overexpression of Rllβ regulatory subunit of protein kinase A in human colon carcinoma cell induces growth arrest and phenotypic changes that are abolished by site-directed mutation of Rllβ Nesterova M;Yokozaki H;McDuffie E;Cho-Chung YS
  20. J Biol Chem v.264 Overexpression of the type Il regulatory subunit of the cAMP-dependent protein kinase eliminates the type Ⅰ holoenzyme in mouse cells Otten AD;McKnight GS
  21. J Biol Chem v.262 Hormonal regulation of the synthesis and mRNA content of the regulatory subunit of cyclic AMP-dependent protein kinase type Ⅱ in the cultured rat ovarian granulosa cells Ratoosh SL;Lifka J;Hedin L;Jahnsen T;Richards J
  22. J Biol Chem v.268 8-Cl-cAMP induces truncatio and down-regulation of the Rlα subunit and up-regulation of the Rllβ subunit of cAMP-dependent protein kinase leading to type Ⅱ holoenzyme-dependent growth inhibition and differentiation of HL-60 leukemia cells Rohlff C;Clair T;Cho-Chung YS
  23. Biochem Biophys Res Commun v.149 Molecular cloning, cDNA structure and deduced amino acid sequence for a type Ⅰ regulatory subunit of cAMP-dependent protein kinase from human testis Sandberge M;Tasken K;Oyen O;Hansson V;Jahnsen T
  24. Korean J Zool v.3 Endogenous gene expression of p53 and regulatory subunit of cyclic AMP-dependent protein kinase in ovarian cancer cells Seo J;Park W;Kim JS;Hwang ES;Lee J-H;Hong SH
  25. J Am Chem v.79 Properties of an adenine ribonucleotide produced with cellular particles, adenosinetriphosphate, magnesium, and adrenaline or glucagon Sutherland EW;Rall TW
  26. Proc Natl Acad Sci USA v.86 Induction of megakaryocytic differentiation and modulation of protein kinase gene expression by site-selective cAMP analogs in K-562 human leukemic cells Tortora G;Clair T;Katsaros D;Ally S;Colamonici O;Neckers LM;Tagliaferri P;Jahnsen T;Robins RK;Cho-Chung YS
  27. FEBS Lett v.242 Site-selective 8-chloroadenosine 3',5'-cyclic monophosphate inhibits transformation and transforming growth factor α production in Ki-ras-transformed rat fibroblasts Tortora G;Ciardiello F;Ally S;Clair T;Salomon DS;Cho-Chung YS
  28. J Biol Chem v.256 Turnover of regulatory subunit of cyclic AMP-dependent protein kinase in S49 mouse lymphoma cells Steinberg RA;Agard DA
  29. Proc Natl Acad Sci USA v.87 An antisense oligodeoxynucleotide targeted against the type Ⅱ regulatory subunit mRNA of protein kinase inhibits cAMP-induced differentiation in HL-60 leukemia cells without affecting phorbol ester effects Tortora G;Clair T;Cho-Chung YS
  30. J Biol Chem v.265 Type Ⅱ regulatory subunit of protein kinase restores cAMP-dependent transcription in a cAMP-unresponsive cell line Tortora G;Cho-Chung YS
  31. Proc Natl Acad Sci USA v.88 Differentiation of HL-60 leukemia by type Ⅰ regulatory subunit antisense oligodeoxynucleotie of cAMP-dependent protein kinase Tortora G;Yokozaki H;Pepe S;Clair T;Cho-Chung YS
  32. Oncogene v.9 The Rlα subunit of protein kinase A controls serum dependency and entry into cell cycle of human mammary epithelial cells Tortora G;Pepe S;Bianco C;Baldassarre G;Budillon A;Clair T;Cho-Chung YS;Bianco AR;Ciardiello F
  33. Cancer Res v.53 An antisense oligodeoxy-nucleotide that depletes Rlα subunit of cyclic AMP-dependent protein kinase induces growth inhibition in human cancer cells Yokozaki H;Budillon A;Tortora G;Meissner S;Beaucage SL;Miki K;Cho-Chung YS