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Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases.

Publication ,  Journal Article
Attiga, FA; Fernandez, PM; Weeraratna, AT; Manyak, MJ; Patierno, SR
Published in: Cancer Res
August 15, 2000

Eicosanoids modulate the interaction of tumor cells with various host components in cancer metastasis. Their synthesis involves the release of arachidonic acid (AA) from cellular phospholipids by phospholipase A2 (PLA2), followed by metabolism by cyclooxygenases (COXs) and lipooxygenases (LOXs). This study aimed to identify the pathway(s) of AA metabolism that are required for the invasion of prostate tumor cells. DU-145 and PC-3 human prostate cancer cell lines were used to test the effect of inhibitors of PLA2, COX, or LOX on the invasion of prostate tumor cells through Matrigel in vitro using the Boyden chamber assay and fibroblast-conditioned medium as the chemoattractant. We used nontoxic doses that did not inhibit simple cell motility and did not decrease clonogenic survival. All of the inhibitors caused a significant reduction in AA release from treated cells compared with control cells, which indicated that the treatments were biochemically active. Invasion through Matrigel was inhibited by the PLA2 inhibitor 4-bromophenacyl bromide (4-BPB), the general COX inhibitor ibuprofen (IB), and the highly selective COX-2 inhibitor NS398. Inhibition of cell invasiveness by 4-BPB (1.0 microM), IB (10.0 microM), and NS398 (10.0 microM) was reversed by the addition of prostaglandin E2 (PGE2). PGE2 alone, however, did not stimulate invasiveness, which suggests that its production is necessary for rendering the cells invasive-permissive but not sufficient for inducing invasiveness. In contrast, we found no significant inhibition of invasion of prostate tumor cells treated with esculetin (1.0 microM) or nordihydroguiaretic acid (1.0 microM), which are specific inhibitors of LOX. We also tested the effect of 4-BPB, IB, NS398, and esculetin on the secretion of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), as key enzymes in the proteolysis of Matrigel during invasion, using gelatin zymograms and Western blots. Cells that received 4-BPB, IB, or NS398, but not esculetin showed a significant reduction in the levels of proMMP-2, MMP-9, and proMMP-9 in the culture medium. DU-145 cells did not secrete TIMP-1, and the drugs did not alter the secretion of TIMP-2. This work highlights the role played by COX in disturbing the balance between MMPs and TIMPs in prostate cancer cells, and it points to the potential use of COX inibitors, especially COX-2 selective inhibitors, in the prevention and therapy of prostate cancer invasion.

Duke Scholars

Published In

Cancer Res

ISSN

0008-5472

Publication Date

August 15, 2000

Volume

60

Issue

16

Start / End Page

4629 / 4637

Location

United States

Related Subject Headings

  • Umbelliferones
  • Tumor Cells, Cultured
  • Tissue Inhibitor of Metalloproteinases
  • Sulfonamides
  • Prostatic Neoplasms
  • Prostaglandins
  • Prostaglandin-Endoperoxide Synthases
  • Phospholipases A2
  • Phospholipases A
  • Oncology & Carcinogenesis
 

Citation

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MLA
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Attiga, F. A., Fernandez, P. M., Weeraratna, A. T., Manyak, M. J., & Patierno, S. R. (2000). Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases. Cancer Res, 60(16), 4629–4637.
Attiga, F. A., P. M. Fernandez, A. T. Weeraratna, M. J. Manyak, and S. R. Patierno. “Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases.Cancer Res 60, no. 16 (August 15, 2000): 4629–37.
Attiga FA, Fernandez PM, Weeraratna AT, Manyak MJ, Patierno SR. Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases. Cancer Res. 2000 Aug 15;60(16):4629–37.
Attiga FA, Fernandez PM, Weeraratna AT, Manyak MJ, Patierno SR. Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases. Cancer Res. 2000 Aug 15;60(16):4629–4637.

Published In

Cancer Res

ISSN

0008-5472

Publication Date

August 15, 2000

Volume

60

Issue

16

Start / End Page

4629 / 4637

Location

United States

Related Subject Headings

  • Umbelliferones
  • Tumor Cells, Cultured
  • Tissue Inhibitor of Metalloproteinases
  • Sulfonamides
  • Prostatic Neoplasms
  • Prostaglandins
  • Prostaglandin-Endoperoxide Synthases
  • Phospholipases A2
  • Phospholipases A
  • Oncology & Carcinogenesis