Skip to main content
SpringerLink
Log in

Forskolin up-regulates metastasis-related phenotypes and molecules via protein kinase B, but not PI-3K, in H7721 human hepato-carcinoma cell line

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Forskolin (FSK) is known as an up-regulator of intracellular cAMP and inhibitor of cancer growth and metastasis. The effects of FSK on the metastasis potential and its mechanisms were studied using a human hepatocarcinoma cell line, H7721. It was found that FSK stimulated cell growth, increased cAMP in the cells, and enhanced the metastasis-related phenotypes, including adhesion to laminin (Ln) and human umbilical vein epithelial cells (HUVEC), chemotactic migration and invasion. These effects were supposed to result from the increase of the SLex expression induced by FSK, since only the monoclonal antibody of SLex showed a significant attenuation of the enhanced metastasis-associated phenotypes. Using H7721 cells transfected with the sense or antisense cDNA of protein kinase B (PKB) and some inhibitors of signal transduction, it was discovered that FSK up-regulated the expression of SLex via PKB, but it was independent of phosphotidylinositide-3-kinase (PI-3K). A subtype of atypical protein kinase C (α-PKC) might also participate in the up-regulation of SLex expression by FSK, and cAMP/PKA pathway is a negative regulator of SLex expression on H7721 cells. It can be concluded that FSK shows a metastasis-promoting effect ex vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Metzger H, Linder E: The positive inotropic-acting forskolin, a potent adenylate cyclase activator. Arzneimittle-Forschung 31: 1248-1250, 1981

    Google Scholar 

  2. Seamon KB, Padgett W, Daly JW: Forskolin: Unique diterpene activator of adenylate cyclase in membranes and intact cells. Proc Natl Acad Sci USA 78: 3363-3367, 1981

    Google Scholar 

  3. Schimmer BP, Schulz P: The roles of cAMP and cAMP-dependent protein kinase in forskolin's actions on Y1 adrenocortical tumor cells. Endocr Res 11: 199-209, 1985

    Google Scholar 

  4. Gamet L, Murat JC, Remaury A, Remesy C, Valet P, Paris H, Denis-Pouxviel C: Vasoactive intestinal peptide and forskolin regulate proliferation of the HT29 human colon adenocarcinoma cell line. J Cell Physiol 150: 501-509, 1992

    Google Scholar 

  5. Lockwood AH, Murphy SK, Borislow S, Lazarus A, Pendergast M: Cellular signal transduction and reversal of malignancy. J Cell Biochem 33: 237-255, 1987

    Google Scholar 

  6. Boghaert ER, Simpson J, Jacob RJ, Lacey T, Walsh JW, Zimmer SG: The effect of dibutyl cAMP on morphological differentiation, growth and invasion in vitro of hamster brain-tumor cell line. A comparative study of db-cAMP effects in 2 and 3 dimensional cultures. Int J Cancer 47: 162-167,1991

    Google Scholar 

  7. Hordijk PL, Verlaan I, Jalink K, Van Corvan EJ, Moolenaar WH: cAMP abrogates the p21ras-mitogen-activated protein kinase pathway in fibroblasts. J Biol Chem 269: 3534-3538, 1994

    Google Scholar 

  8. Chai XY, Qi H, Chen HL: Protein kinase and cell differentiation. Inhibition of tyrosine protein kinase by two inducers of differentiation. Chinese Biochem J 9: 162-167, 1993

    Google Scholar 

  9. Chai XY, Chen HL: Expression of oncogenes during induced differentiation of human hepatocarcinoma cell line. Chin J Cancer Res 6: 3-8, 1994

    Google Scholar 

  10. Liu F, Qi HL, Chen HL: Regulation of differentiation-and proliferation-inducers on Lewis antigens, α-fucosyltransferase and metastatic potential in hepatocarcinoma cells. Brit J Cancer 268: 3501-3512, 2001

    Google Scholar 

  11. Dong SC, Ren JX, Yang XP, Gu JX, Chen HL: Regulation of N-acetylglucosaminyl-transferase V and III by differentiation inducers and proliferation stimulator. Chinese J Biochem Biophys 26: 535-540, 1994

    Google Scholar 

  12. Brockhausen I, Narasimhan S, Schachter H: The biosynthesis of highly branched N-glycans. Studies on the sequential pathway and functional role of N-acetylglucosaminyl-transferase I, II, III, IV, V and VI. Biochimie 70: 1521-1533, 1988

    Google Scholar 

  13. Dennis JW, Laferte S: Tumor cell surface carbohydrate and the metastatic phenotype. Cancer Metastasis Rev 5: 185-204, 1987

    Google Scholar 

  14. Fernandes B, Sagman U, Auger M, Demetrio M, Dennis JW: β1,6 branched oligosaccharides as a marker of tumor progression in human breast and neoplasia. Cancer Res 51: 718-723, 1991

    Google Scholar 

  15. Varki LA: Selectin ligands. Proc Natl Acad Sci USA 91: 7390-7397, 1994

    Google Scholar 

  16. Hakomori SI: Tumor malignancy defined by aberrant glycosylation and sphingo (glyco) lipid metabolism. Cancer Res 56: 5309-5318, 1996

    Google Scholar 

  17. Kansas GS: Selectins and their ligands: Current concepts and controversies. Blood 88: 3259-3287, 1996

    Google Scholar 

  18. Takada A, Ohmori K, Yoneda T, Tsuyuoka K, Hasegawa A, Kiso M, Kannagi R: Contribution of carbohydrate antigens sialyl Lewis A and sialyl Lewis X to adhesion of human cancer cells to vascular endothelium. Cancer Res 53: 354-361, 1993

    Google Scholar 

  19. Liu F, Qi HL, Zhang Y, Zhang XY, Chen HL: Transfection of c-erbB2/neu gene up-regulates the expression of sialyl Lewis X, α1,3 fucosyl-transferase VII and metastatic potential in human hepatocarcinoma cell line. Eur J Biochem 268: 3501-3512, 2001

    Google Scholar 

  20. Welch DR: Technical considerations for studying cancer metastasis in vivo. Clin Exp Metastasis 15: 272-306, 1997

    Google Scholar 

  21. Guo HB, Shen ZH, Huang CX, Huang Y, Chen HL: Modification on the basal activity of N-acetylglucosaminyltransferase V by phosphatidylinositol-3-kinase/protein kinase B signaling pathways in human hepatocarcinoma cells. Glycoconj J 17: 315-322, 2000

    Google Scholar 

  22. Liu F, Qi HL, Chen HL: Effects of all-trans retinoic acid and epidermal growth factor on the expression of nm23-H1 in human hepatocarcinoma cells. J Cancer Res Clin Oncol 126, 85-90, 2000

    Google Scholar 

  23. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin-phenol reagent. J Biol Chem 193: 265-271, 1951

    Google Scholar 

  24. Kudo T, Ikehara Y, Togayachi A, Morozumi K, Watanabe M, Nakamura M, Nishihara S, Narimatsu H: Up-regulation of a set of glycosyltransferase genes in human colorectal cancer. Lab Invest 78: 797-811, 1998

    Google Scholar 

  25. Cohen P, Alessi DR, Cross DAE: PDK-1, one of the missing links in insulin transduction. FEBS Lett 410: 3-10, 1997

    Google Scholar 

  26. Zhou X, Lu X, Richard C, Xiong W, Litchfield DW, Bittman R, Authur G: 1-O-octadecyl-2-metyl-glycerophophocholine inhibits the transduction of growth signals via the MAPK cascade in cultured MCF-7 cells. J Clin Invest 98: 937-944, 1996

    Google Scholar 

  27. Powis G, Seewald MJ, Gratas C, Melder D, Riebow J, Modest EJ: Selective inhibition of phosphatidylinositol phospholipase C by cytotoxic ether lipid analogues. Cancer Res 52: 2835-2840, 1992

    Google Scholar 

  28. Nakamura SI: Phosphatidylcholine hydrolysis and protein kinase C activation for intracellular signaling network. J Lipid Mediator Cell Signal 14: 197-202, 1996

    Google Scholar 

  29. Herbert JM, Augereau JM, Gleye J, Maffrand JP: Chelerythrine is a potent and specific inhibitor of protein kinase C. Biochem Biophys Res Commun 172: 993-999, 1990

    Google Scholar 

  30. Kent KC, Mii S, Harrington EO, Chang JD, Mallette S, Ware JA. Requirement for protein kinase C activation in basic fibroblast growth factor-induced human endothelial cell proliferation. Circ Res 77: 231-238, 1995

    Google Scholar 

  31. Guo HB, Zhang QS, Chen HL: Effect of H-ras and v-sis overexpression on the N-acetylglucosaminyltransferse V and metastasis-related phenotypes in human hepatocarcinoma cells. J Cancer Res Clin Oncol 126: 263-270, 2000

    Google Scholar 

  32. Guo HB, Liu F, Zhao JH, Chen HL: Down-regulation of N-Acetylglucosaminyl-transferase V by tumorigenesis-or metastasis-suppressor gene and its relation to metastatic potential of human hepatocarcinoma cells. J Cell Biochem 79: 370-385, 2000

    Google Scholar 

  33. Agarwal KC, Parks RE Jr: Forskolin: A potential antimetastatic agent. Int J Cancer 32: 801-804, 1983

    Google Scholar 

  34. Westermann P, Knoblich M, Maier O, Lindschau C, Haller H: Protein kinase C bound to the Golgi apparatus supports the formation of constitutive transport vesicles. Biochem J 320: 651-658, 1996

    Google Scholar 

  35. Landanna C, Mochly-Rosen D, Liron T, Constantin G, Butcher EC: Evidence of zeta protein kinase C involvement in polymorphonuclear neutrophile integrin-dependent adhesion and chemotaxis. J Biol Chem 273: 30306-30315, 1998

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, School of Medicine, Su-zhou University, Su-zhou, 215007, China

    Shi-liang Wu

  2. Key Laboratory of Glycoconjugate Research, Ministry of Health, Department of Biochemistry, Changhai Medical College of Fu-Dan University, Shanghai, 200032, China

    Jun Ma, Hui-ling Qi, Ying Zhang, Xia-ying Zhang & Hui-li Chen

Authors
  1. Shi-liang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui-ling Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xia-ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hui-li Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, Sl., Ma, J., Qi, Hl. et al. Forskolin up-regulates metastasis-related phenotypes and molecules via protein kinase B, but not PI-3K, in H7721 human hepato-carcinoma cell line. Mol Cell Biochem 254, 193–202 (2003). https://doi.org/10.1023/A:1027392212341

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1027392212341

Search

Navigation