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- W2989686188 abstract "831 Many chemotherapeutic agents cause cytotoxicity by initiating apoptosis. Defects in apoptosis contribute to cancer therapy failure and the emergence of resistant disease. Identifying new molecules that confer resistance to cancer therapy allows design of strategies that restore drug sensitivity to resistant cancers. Platelet endothelial cell adhesion molecule-1 (PECAM-1), a homophilic binding member of the immunoreceptor tyrosine-based inhibitory motif (ITIM) family of inhibitory receptors, has previously been shown to potently suppress mitochondrial-dependent, Bax-mediated apoptosis. PECAM-1 expression has been reported on a variety of human malignancies, including leukemias, cervical cancer, multiple myeloma, angiosarcoma, salivary gland malignancy, and breast cancer, but the significance of this expression has not been well-defined. Here we show that PECAM-1 expression can inhibit apoptosis induced by the genotoxic chemotherapeutic agents cisplatin and etoposide. HEK293 and REN mesothelioma cells lacking PECAM-1 displayed much higher caspase activity and nuclear condensation after drug treatment than did cells expressing PECAM-1. The protective effect of PECAM-1 is, in part, mediated by the ITIM domains within its cytoplasmic tail, as mutation of ITIM tyrosines prevented full protection. In addition, a PECAM-1 mutant lacking homophilic binding ability was not fully protective. Thus, PECAM-1 appears to confer resistance to cell death via both cell-cell communication and intracellular signaling via its ITIM domains. Finally, when stable cell lines expressing PECAM-1 were treated with etoposide for 48 hours and subsequently cultured up to five weeks, the surviving cells had a greater than 40% increase in the median number of PECAM-1 molecules expressed on their surface when compared to untreated cells, indicating that cells with higher PECAM-1 expression are more likely to survive treatment with DNA-damaging chemotherapy. Taken together, these studies suggest PECAM-1 attenuates apoptosis in response to DNA damage and that this receptor is capable of conferring resistance to genotoxic chemotherapeutic agents. Furthermore, PECAM-1 expression on human malignancies may increase the likelihood of developing resistance to chemotherapeutic treatment, making this molecule a possible prognostic indicator of treatment response. Identifying ways in which to abolish PECAM-1’s protective effect may be an effective adjuvant therapy for patients whose cancers express this cell-surface molecule." @default.
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- W2989686188 date "2005-05-01" @default.
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- W2989686188 title "The cell-adhesion and signaling molecule PECAM-1 as a molecular mediator of genotoxic chemotherapy resistance" @default.
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