The cell-adhesion and signaling molecule PECAM-1 is a molecular mediator of resistance to genotoxic chemotherapy.
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.
Bergom
Carmen
C
Blood Research Institute, Blood Center of Wisconsin, and Department of Cell Biology, Medical College of Wisconsin, Milwaukee, Wisconsin 53201, USA.
Goel
Reema
R
Paddock
Cathy
C
Gao
Cunji
C
Newman
Debra K
DK
Matsuyama
Shigemi
S
Newman
Peter J
PJ
D017209:Apoptosis; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D004730:Endothelium, Vascular / Q000502:physiology; D017353:Gene Deletion; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D019169:Jurkat Cells; D008654:Mesothelioma; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014470:Umbilical Cord
D047908:Intracellular Signaling Peptides and Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011994:Recombinant Proteins; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases