The cell-adhesion and signaling molecule PECAM-1 is a molecular mediator of resistance to genotoxic chemotherapy

Cancer Biol Ther. 2006 Dec;5(12):1699-707. doi: 10.4161/cbt.5.12.3467. Epub 2006 Dec 30.


Defects in the regulation of apoptotic pathways have been implicated in the emergence of cancers resistant to chemotherapy-induced cell death. Identification of novel signaling molecules that influence cell survival has the potential to facilitate the development of new cancer therapies. The cell adhesion and signaling molecule, PECAM-1, is expressed in many hematopoietic and endothelial cell malignancies, and has previously been shown to suppress mitochondrial-dependent, Bax-mediated apoptosis. The ability of PECAM-1 to influence tumor cell survival following exposure to chemotherapeutic agents, however, is not known. Here we show that, when overexpressed in HEK293 and REN mesothelioma cells, PECAM-1 confers resistance to apoptosis induced by the DNA-damaging chemotherapeutic agent, etoposide. Surprisingly, PECAM-1-mediated cytoprotection was found to be largely independent of its ability to form a signaling complex with the protein-tyrosine phosphatase SHP-2, as virtually no tyrosine phosphorylation of, or SHP-2 association with, PECAM-1 could be detected after etoposide treatment. Furthermore, PECAM-1 retained its ability to protect against chemotherapy-induced apoptosis in cells with SHP-2 levels significantly reduced using SHP-2-specific siRNA, and in cells in which Erk1/2--a downstream effector of SHP-2--had been inhibited. Finally, to determine whether endogenous PECAM-1 confers resistance to chemotherapy-induced apoptosis in lymphoid malignancies and endothelial cells, we used a lentiviral vector to stably express PECAM-1-specific siRNA in the Jurkat leukemia cell line and human umbilical vein endothelial cells (HUVECs). siRNA-expressing Jurkat cells with a 70% reduction of PECAM-1 expression were significantly more sensitive to chemotherapy-induced apoptosis. HUVECs with PECAM-1 expression reduced 75% were also markedly more sensitive to chemotherapy-induced cell death. Taken together, these data demonstrate that endogenous PECAM-1 expression on lymphoid cancers confers resistance to apoptosis, and that lowering PECAM-1 expression in lymphoid malignancies can render them more susceptible to chemotherapy-induced apoptosis. In addition, reducing PECAM-1 levels in the tumor endothelium may aid in low-dose, anti-angiogenic therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Adhesion
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Drug Resistance, Neoplasm*
  • Endothelium, Vascular / physiology
  • Gene Deletion
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Jurkat Cells
  • Mesothelioma
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Platelet Endothelial Cell Adhesion Molecule-1 / physiology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Transfection
  • Umbilical Cord


  • Intracellular Signaling Peptides and Proteins
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Recombinant Proteins
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases