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The TMPRSS2:E-twenty-six (ETS) gene fusion occurs frequently in a high proportion of patients with prostate cancer (PCa) in Western countries, and the aberrant expression of TMPRSS2: v-ETS avian erythroblastosis virus E26 oncogene homolog (ERG), the most common form of the corresponding protein, can regulate cell migration and contribute to tumor invasion and metastasis. However, its association with other cellular events, and in particular, cell death, remain unknown. To examine the function of such fusion genes, an expression plasmid containing the TMPRSS2:ERG (T1/E5) sequence (ΔERG) from a patient sample was constructed and transiently transfected into DU145 cells, which do not express the fusion gene. It was found that the overexpression of ΔERG significantly inhibited the ability of cisplatin to induce apoptosis in DU145 cells. By contrast, VCaP cells, which do contain TMPRSS2:ERG, were sensitized to cisplatin-induced apoptosis through siRNA inhibition of the fusion gene. To elucidate the underlying mechanism, a stable cell line expressing the ΔERG gene was constructed. Expression of ΔERG did not affect cell migration, but did protect cells from DNA damage and apoptosis induced by cisplatin. Furthermore, knockdown of ΔERG by short interfering RNA resulted in cells regaining their sensitivity to cisplatin. Finally, the gene coding for activating transcription factor 5, which is important for cell survival, may be upregulated by ΔERG. Taken together, these data point to a new function of the TMPRSS2:ERG fusion gene in regulating the apoptotic pathway. [ABSTRACT FROM AUTHOR]

DNA-damaging agents have been reported to be associated with cardiovascular complications, however, the underlying mechanisms remain to be clarified. In the present study, the possible vascular effects of cisplatin was assessed by measuring its effects on the contractile function of thoracic aortic rings dissected from Sprague-Dawley (SD) rats. Contraction of the aortic ring was induced by 60 mM KCl or 10-6 M phenylephrine (PE) in an ex vivo perfusion system. Cisplatin (200 µM) counteracted KCl- and PE-induced contraction by 57.6 and 91.8%, respectively, in endothelium-intact aortic rings. Similar results were obtained in endothelium-denuded aortas. Electromicroscopy analysis revealed severe damage to blood vessel walls in vivo by cisplatin. In addition, cisplatin significantly inhibited adenosine triphosphate (ATP)-induced intracellular Ca2+ concentration ([Ca2+]i) increases in human umbilical vein endothelial cells (HUVECs). These results suggested that the DNA-damaging agent cisplatin can affect the contractile function of thoracic aortas. In addition, in accordance with its DNA-damaging properties, the cardiovascular toxicity of cisplatin may be the result of its direct cytotoxicity. [ABSTRACT FROM AUTHOR]