Effects of α-difluoromethylornithine on thrombospondin-1 production by human breast cancer cells

  • Authors:
    • Andrea Manni
    • Terry Rager
    • Scot R. Kimball
    • Leonard S. Jefferson
    • Sharlene Washington
    • Xin Hu
    • Michael F. Verderame
  • View Affiliations

  • Published online on: November 1, 2007     https://doi.org/10.3892/ijo.31.5.1187
  • Pages: 1187-1191
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Abstract

We have previously observed that inhibition of polyamine biosynthesis with α-difluoromethylornithine (DFMO) upregulates production of thrombospondin-1 (TSP-1), an extracellular matrix protein with potent anti-angiogenic and antimetastatic properties, by MDA-MB-435 human breast cancer cells in culture. The present experiments were designed to investigate the mechanisms by which DFMO regulates TSP-1 production in this system. 35S-methionine pulse chase experiments indicated that DFMO administration increased TSP-1 synthesis by approximately 6-fold, while it slightly but significantly decreased protein half-life from 35 to 28 min. DFMO treatment increased steady state TSP-1 mRNA levels by 2-fold in MDA-MB-435 cells. TSP-1 promoter reporter studies indicated that this increase was largely due to activation of transcription. Analysis of distribution of TSP-1 mRNA levels between non-polysomal, subpolysomal and polysomal fractions in control and DFMO-treated cells suggested a major stimulatory effect of the drug on TSP-1 translation. A similar increase in TSP-1 transcription and translation in response to DFMO treatment was also observed in vivo in MDA-MB-435 breast cancer xenografts. Surprisingly however, we failed to detect an increase in TSP-1 protein as assessed by Western blot analysis. The reason for this unexpected finding is unknown but may be due to DFMO-induced stimulation of TSP-1 secretion into the systemic circulation, thus preventing its accumulation within the tumor.

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November 2007
Volume 31 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Manni, A., Rager, T., Kimball, S.R., Jefferson, L.S., Washington, S., Hu, X., & Verderame, M.F. (2007). Effects of α-difluoromethylornithine on thrombospondin-1 production by human breast cancer cells. International Journal of Oncology, 31, 1187-1191. https://doi.org/10.3892/ijo.31.5.1187
MLA
Manni, A., Rager, T., Kimball, S. R., Jefferson, L. S., Washington, S., Hu, X., Verderame, M. F."Effects of α-difluoromethylornithine on thrombospondin-1 production by human breast cancer cells". International Journal of Oncology 31.5 (2007): 1187-1191.
Chicago
Manni, A., Rager, T., Kimball, S. R., Jefferson, L. S., Washington, S., Hu, X., Verderame, M. F."Effects of α-difluoromethylornithine on thrombospondin-1 production by human breast cancer cells". International Journal of Oncology 31, no. 5 (2007): 1187-1191. https://doi.org/10.3892/ijo.31.5.1187