Tumorigenic transformation of immortalized ECV endothelial cells by cyclooxygenase-1 overexpression.
The cyclooxygenase (Cox) enzyme catalyzes the rate-limiting oxidative and peroxidative enzymatic steps in the biosynthesis of prostanoids. Both Cox-1 and -2 genes encode the two isoenzymes that carry out similar enzymatic steps. Enhanced Cox activity is associated with proliferative diseases such as colon cancer. To determine if a cause and effect relationship exists between Cox isoenzyme overexpression and tumorigenesis, the human Cox-1 and Cox-2 isoenzymes were transfected into ECV immortalized endothelial cells. Although numerous clones of Cox-1 expressing cells were obtained, Cox-2 overexpression resulted in growth disadvantage and increased cell death. In contrast, Cox-1 overexpressing cells expressed high levels of the functional Cox-1 polypeptide in the endoplasmic reticulum and the nucleus. In vitro proliferation of these cells was reduced compared with vector-transfected ECV cells. Cox-1 overexpression also enhanced the tumor necrosis factor-alpha-induced apoptosis of ECV cells 2-fold. In contrast to the in vitro behavior, ECV-Cox-1 cells proliferated aggressively and formed tumors in athymic "nude" mice, whereas the vector-transfected counterparts did not. The growth of Cox-1-induced tumors was not inhibited by indomethacin, suggesting a nonprostanoid function of Cox-1. ECV-Cox-1-derived tumors were angiosarcoma-like and contained numerous host-derived neovessels. These data suggest that Cox-1 overexpression in immortalized ECV endothelial cells results in nuclear localization of the polypeptide and tumorigenesis.
Narko
K
K
Department of Clinical Chemistry and Obstetrics and Gynecology, Haartman Institute, Helsinki University, Helsinki, Finland.
Ristimäki
A
A
MacPhee
M
M
Smith
E
E
Haudenschild
C C
CC
Hla
T
T
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D014162:Transfection; D014183:Transplantation, Heterologous
D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse