Angiogenesis inhibitors target the endothelial cell cytoskeleton through altered regulation of heat shock protein 27 and cofilin

Susan M. Keezer, Susan E. Ivie, Henry C. Krutzsch, Anita Tandle, Steven K. Libutti, David D. Roberts

Research output: Contribution to journalArticle

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Abstract

Inhibition of angiogenesis has emerged as a key focus for the treatment of cancer, necessitating a better understanding of the downstream molecular targets of angiogenesis inhibitors. Endostatin, thrombospondin-1, fumagillin, and its synthetic derivative, TNP-470, are potent inhibitors of endothelial cell proliferation and migration in culture and of angiogenesis in vivo. To identify targets that mediate the effects of these inhibitors, we compared two-dimensional gel electrophoresis patterns from lysates of treated and untreated human endothelial cells. Among the proteins identified were cofilin and hsp27, two proteins involved in actin dynamics. Western blotting and immunofluorescence experiments confirmed that the phosphorylation states and subcellular localization of these two proteins were affected by all of the inhibitors tested and that treated cells had a more extensive network of actin stress fibers and more numerous focal adhesion plaques compared with untreated cells. Endothelial monocyte activating polypeptide II, another angiogenesis inhibitor, elicited the same response in the actin cytoskeleton and focal adhesions of endothelial cells. This more adherent phenotype may explain the shared ability of these inhibitors to block endothelial migratory signals. Starting with a proteomics approach, we have identified common effector molecules used by a panel of angiogenesis inhibitors that perturb the cytoskeleton to prevent endothelial migration.

Original languageEnglish (US)
Pages (from-to)6405-6412
Number of pages8
JournalCancer Research
Volume63
Issue number19
StatePublished - Oct 1 2003
Externally publishedYes

Fingerprint

Actin Depolymerizing Factors
HSP27 Heat-Shock Proteins
Focal Adhesions
Angiogenesis Inhibitors
Cytoskeleton
Endothelial Cells
Actins
Endostatins
Thrombospondin 1
Stress Fibers
Proteins
Electrophoresis, Gel, Two-Dimensional
Actin Cytoskeleton
Proteomics
Cell Movement
Fluorescent Antibody Technique
Western Blotting
Phosphorylation
Cell Proliferation
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Keezer, S. M., Ivie, S. E., Krutzsch, H. C., Tandle, A., Libutti, S. K., & Roberts, D. D. (2003). Angiogenesis inhibitors target the endothelial cell cytoskeleton through altered regulation of heat shock protein 27 and cofilin. Cancer Research, 63(19), 6405-6412.

Angiogenesis inhibitors target the endothelial cell cytoskeleton through altered regulation of heat shock protein 27 and cofilin. / Keezer, Susan M.; Ivie, Susan E.; Krutzsch, Henry C.; Tandle, Anita; Libutti, Steven K.; Roberts, David D.

In: Cancer Research, Vol. 63, No. 19, 01.10.2003, p. 6405-6412.

Research output: Contribution to journalArticle

Keezer, SM, Ivie, SE, Krutzsch, HC, Tandle, A, Libutti, SK & Roberts, DD 2003, 'Angiogenesis inhibitors target the endothelial cell cytoskeleton through altered regulation of heat shock protein 27 and cofilin', Cancer Research, vol. 63, no. 19, pp. 6405-6412.
Keezer SM, Ivie SE, Krutzsch HC, Tandle A, Libutti SK, Roberts DD. Angiogenesis inhibitors target the endothelial cell cytoskeleton through altered regulation of heat shock protein 27 and cofilin. Cancer Research. 2003 Oct 1;63(19):6405-6412.
Keezer, Susan M. ; Ivie, Susan E. ; Krutzsch, Henry C. ; Tandle, Anita ; Libutti, Steven K. ; Roberts, David D. / Angiogenesis inhibitors target the endothelial cell cytoskeleton through altered regulation of heat shock protein 27 and cofilin. In: Cancer Research. 2003 ; Vol. 63, No. 19. pp. 6405-6412.
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