16-kDa prolactin inhibits endothelial cell migration by down-regulating the Ras-Tiam1-Rac1-Pak1 signaling pathway

Sok Hyong Lee, Jeannette Kunz, Sue Hwa Lin, Li Yuan Yu-Lee

Research output: Contribution to journalArticle

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Abstract

Angiogenesis plays a key role in promoting tumorigenesis and metastasis. The 16-kDa fragment of prolactin (16k PRL) is an NH2-terminal natural breakdown fragment of the intact 23-kDa prolactin and has been shown to have potent antiangiogenic and antitumor activities. The mechanism(s) involved in the action of 16k PRL in endothelial cells remains unclear. In this study, we showed that 16k PRL reduced rat aortic endothelial cell (RAEC) migration in a wound-healing assay and in a Matrigel tube formation assay, suggesting that 16k PRL inhibits endothelial cell migration, an important activity involved in angiogenesis and tumorigenesis. We further investigated how 16k PRL attenuates endothelial cell migration. We first showed that RAEC migration is mediated through the Rho GTPase Rac1, as Rac1 inhibition by the Rac1-specific inhibitor NSC27366 or Rac1 knockdown by small interfering RNA both blocked RAEC migration. We next showed that 16k PRL reduced the activation of Rac1 in a concentration-dependent manner. Furthermore, 16k PRL inhibition of Rac1 is mediated through the suppression of T lymphoma invasion and metastasis 1 (Tiam1) and its upstream activator Ras in a phosphoinositide-3-kinase-independent manner. 16k PRL also down-regulated the phosphorylation of the downstream effector of Rac1, p21-activating kinase 1 (Pak1), and inhibited its translocation to the leading edge of migrating cells. Thus, 16k PRL inhibits cell migration by blocking the Ras-Tiam1-Rac1-Pak1 signaling pathway in endothelial cells.

Original languageEnglish
Pages (from-to)11045-11053
Number of pages9
JournalCancer Research
Volume67
Issue number22
DOIs
Publication statusPublished - Nov 15 2007
Externally publishedYes

Fingerprint

Prolactin
Cell Movement
Lymphoma
Phosphotransferases
Endothelial Cells
Neoplasm Metastasis
Carcinogenesis
rho GTP-Binding Proteins
1-Phosphatidylinositol 4-Kinase
Wound Healing
Small Interfering RNA
Phosphorylation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

16-kDa prolactin inhibits endothelial cell migration by down-regulating the Ras-Tiam1-Rac1-Pak1 signaling pathway. / Lee, Sok Hyong; Kunz, Jeannette; Lin, Sue Hwa; Yu-Lee, Li Yuan.

In: Cancer Research, Vol. 67, No. 22, 15.11.2007, p. 11045-11053.

Research output: Contribution to journalArticle

Lee, Sok Hyong ; Kunz, Jeannette ; Lin, Sue Hwa ; Yu-Lee, Li Yuan. / 16-kDa prolactin inhibits endothelial cell migration by down-regulating the Ras-Tiam1-Rac1-Pak1 signaling pathway. In: Cancer Research. 2007 ; Vol. 67, No. 22. pp. 11045-11053.
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