Skip to main content

Advertisement

SpringerLink
Log in

Betulinic acid inhibits the expression of hypoxia-inducible factor 1α and vascular endothelial growth factor in human endometrial adenocarcinoma cells

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

Abstract

Although betulinic acid (BA) is known to induce apoptosis and antiangiogenic response in tumor cells, the underlying mechanism of its action is unknown. Deregulation of tissue collagen metabolism is one of the consequences of neoplastic transformation. The final step of collagen degradation is mediated by prolidase [E.C.3.4.13.9] which may play a role in angiogenesis. The formation of new blood vessels is regulated by the hypoxia-inducible factor 1 (HIF-1). The expression of HIF-1 correlates with hypoxia-induced angiogenesis as a result of the induction of vascular endothelial cell growth factor (VEGF). Since BA evokes anticancer activity, its effect on collagen biosynthesis, HIF-1α and VEGF expressions, as well as prolidase activity and expression was studied in cultured endometrial adenocarcinoma (EA) cells. It was found that BA inhibits collagen biosynthesis in EA cells (5[3H] proline incorporation assay). It was accompanied by a parallel decrease in prolidase activity and expression and decrease in expressions of α1 and α2 integrins, HIF-1α, and VEGF (western immunoblot analysis) in cultured human EA cells. The data suggest that BA may have anti-angiogenic potential by inhibition of prolidase, HIF-1α and VEGF expressions, and inhibition of collagen biosynthesis.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Mukherjee PK, Saha K, Das J, Pal M, Saha BP (1997) Studies on the anti-inflammatory activity of rhizomes of Nelumbo nucifera. Planta Med 63:367–369

    Article  CAS  PubMed  Google Scholar 

  2. Yun Y, Han S, Park E et al (2003) Immunomodulatory activity of betulinic acid by producing proinflammatory cytokines and activation of macrophages. Arch Pharm Res 26:1087–1095

    Article  CAS  PubMed  Google Scholar 

  3. Wen CC, Kuo YH, Jan JT et al (2007) Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J Med Chem 50:4087–4095

    Article  CAS  PubMed  Google Scholar 

  4. Fulda S, Jeremias I, Steiner HH, Pietsch T, Debatin KM (1999) Betulinic acid: a new cytotoxic agent against malignant brain–tumor cells. Int J Cancer 82:435–441

    Article  CAS  PubMed  Google Scholar 

  5. Cichewicz RH, Kouzi SA (2004) Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection. Med Res Rev 24:90–114

    Article  CAS  PubMed  Google Scholar 

  6. Eiznhamer DA, Xu ZQ (2004) Betulinic acid: a promising anticancer candidate. IDrugs 7:359–373

    CAS  PubMed  Google Scholar 

  7. Chintharlapalli S, Papineni S, Ramaiah SK, Safe S (2007) Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res 67:2816–2823

    Article  CAS  PubMed  Google Scholar 

  8. Bissel M (1981) How does extracellular matrix direct gene expression? J Theor Biol 99:31–68

    Article  Google Scholar 

  9. Carey DJ (1991) Control of growth and differentiation of vascular cells by extracellular matrix. Ann Rev Physiol 53:161–177

    Article  CAS  Google Scholar 

  10. Ruoslahti E (1992) Control of cell motility and tumor invasion by extracellular matrix interaction. Br J Cancer 66:239–242

    CAS  PubMed  Google Scholar 

  11. Arata J, Tada J, Yamada T, Oono T, Yasutomi H, Oka E (1991) Angiopathic pathogenesis of clinical manifestations in prolidase deficiency. Arch Dermatol 127:124–125

    Article  CAS  PubMed  Google Scholar 

  12. Choi KS, Bae MK, Jeong JW, Moon HE, Kim KW (2003) Hypoxia-induced angiogenesis during carcinogenesis. J Biochem Mol Biol 36:120–127

    CAS  PubMed  Google Scholar 

  13. Kolev Y, Uetake H, Iida S, Ishikawa T, Kawano T, Sugihara K (2007) Prognostic significance of VEGF expression in correlation with COX-2, microvessel density, and clinicopathological characteristics in human gastric carcinoma. Ann Surg Oncol 14:2738–2747

    Article  PubMed  Google Scholar 

  14. Myara I, Charpentier C, Lemonnier A (1982) Optimal conditions for prolidase assay by proline colorimetric determination: application to imidopeptiduria. Clin Chim Acta 125:193–205

    Article  CAS  PubMed  Google Scholar 

  15. Lowry OH, Rosebrough NI, Farr AL, Randall RJ (1951) Protein measurement with the Folin reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  16. Oyamada I, Pałka J, Schalk EM, Takeda K, Peterkofsky B (1990) Scorbutic and fasted guinea pig sera contain an insulin-like growth factor I reversible inhibitor of proteoglycan and collagen synthesis in chick embryo chondrocytes and adult human skin fibroblasts. Arch Biochem Biophys 276:85–93

    Article  CAS  PubMed  Google Scholar 

  17. Peterkofsky B, Chojkier M, Bateman J (1982) Determination of collagen synthesis in tissue and cell culture system. In: Furthmay H (ed) Immunochemistry of the extracellular matrix. CRC Press, Boca Raton, FL, pp 19–47

    Google Scholar 

  18. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  19. Pałka JA, Phang JM (1997) Prolidase activity in fibroblasts is regulated by interaction of extracellular matrix with cell surface integrin receptors. J Cell Biochem 67:166–175

    PubMed  Google Scholar 

  20. Zuco V, Supino R, Righetti SC et al (2002) Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Lett 175:17–25

    Article  CAS  PubMed  Google Scholar 

  21. Mock WL, Green PC, Boyer KD (1990) Specificity and pH dependence for acylproline cleavage by prolidase. J Biol Chem 265:19600

    CAS  PubMed  Google Scholar 

  22. Surażyński A, Palka J, Wolczynski S (2001) Phosphorylation of prolidase increases the enzyme activity. Mol Cell Biochem 220:95–101

    Article  PubMed  Google Scholar 

  23. Surażyński A, Miltyk W, Pałka J, Phang JM (2008) Prolidase-dependent regulation of collagen biosynthesis. Amino Acids 35:731–738

    Article  PubMed  CAS  Google Scholar 

  24. Surazynski A, Donald SP, Cooper SK et al (2008) Extracellular matrix and HIF-1 signaling: the role of prolidase. Int J Cancer 122:1435–1440

    Article  CAS  PubMed  Google Scholar 

  25. Jaakkola P, Mole DR, Tian YM et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472

    Article  CAS  PubMed  Google Scholar 

  26. Jacob SW, Herschler R (1986) Pharmacology of DMSO. Cryobiology 1:14–27

    Article  Google Scholar 

  27. Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514

    Article  CAS  PubMed  Google Scholar 

  28. Morley P, Whitfield JF (1993) The differentiation inducer, dimethyl sulfoxide, transiently increases the intracellular calcium ion concentration in various cell types. J Cell Physiol 156:219–225

    Article  CAS  PubMed  Google Scholar 

  29. Mottet D, Michel G, Renard P, Ninane N, Raes M, Michiels C (2003) Role of ERK and calcium in the hypoxia-induced activation of HIF-1. J Cell Physiol 194:30–44

    Article  CAS  PubMed  Google Scholar 

  30. Senger DR, Claffey KP, Benes JE, Perruzzi CA, Sergiou AP, Detmar M (1997) Angiogenesis promoted by vascular endothelial growth factor: regulation through α1β1 and α2β1 integrins. Proc Natl Acad Sci USA 94:13612–13617

    Article  CAS  PubMed  Google Scholar 

  31. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613

    CAS  PubMed  Google Scholar 

  32. Jiang BH, Rue E, Wang GL, Roe R, Semenza GL (1996) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271:17771–17778

    Article  CAS  PubMed  Google Scholar 

  33. Gleadle JM, Ratcliffe PJ (1997) Induction of hypoxia-inducible factor-1, erythropoietin, vascular endothelial growth factor, and glucose transporter-1 by hypoxia: evidence against a regulatory role for Src kinase. Blood 89:503–509

    CAS  PubMed  Google Scholar 

  34. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawker AM, Yu AY, Semenza GL (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12:149–162

    Article  CAS  PubMed  Google Scholar 

  35. Sulkowska M, Wincewicz A, Sulkowski S, Koda M, Kanczuga-Koda L (2009) Relations of TGF-beta1 with HIF-1 alpha, GLUT-1 and longer survival of colorectal cancer patients. Pathology 41:254–260

    Article  CAS  PubMed  Google Scholar 

  36. Potter C, Harris AL (2004) Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle 3:164–167

    CAS  PubMed  Google Scholar 

  37. Robertson N, Potter C, Harris AL (2004) Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res 64:6160–6165

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, Medical University in Bialystok, Kilińskiego 1, 15-089, Bialystok, Poland

    Ewa Karna, Lukasz Szoka & Jerzy A. Palka

Authors
  1. Ewa Karna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lukasz Szoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jerzy A. Palka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jerzy A. Palka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karna, E., Szoka, L. & Palka, J.A. Betulinic acid inhibits the expression of hypoxia-inducible factor 1α and vascular endothelial growth factor in human endometrial adenocarcinoma cells. Mol Cell Biochem 340, 15–20 (2010). https://doi.org/10.1007/s11010-010-0395-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-010-0395-8

Keywords

Search

Navigation