Urothelial cells malignantly transformed by exposure to cadmium (Cd(+2)) and arsenite (As(+3)) have increased resistance to Cd(+2) and As(+3)-induced cell death.
This laboratory has shown that both Cd(+2) and As(+3) can malignantly transform human urothelial cells. The present study examined metal resistance and the mechanism of cell death when the parental and malignantly transformed UROtsa cells were exposed to Cd(+2) and As(+3). It was shown that the malignantly transformed UROtsa cells were more resistant to the toxic effects of both metals. The assessment of the mode of cell death demonstrated that the parental UROtsa cells died by both apoptosis and necrosis when exposed to either metal. It was shown that apoptosis was the more prominent mechanism of cell death, accounting for over 50% of cell death. Apoptotic cell death was determined by the observation of fragmented nuclei using 4',6-diamidino-2-phenylindole staining, the formation of a DNA ladder, and the detection of cleaved caspase-3 and caspase-9 products in the cell lysates. Necrotic cell death was determined by measuring the release of lactate dehydrogenase into the growth medium. It was determined that the extent of apoptosis of the malignantly transformed UROtsa cells was decreased and that the extent of necrosis was increased compared to the parental UROtsa cells. These observations are consistent with in vivo studies which suggest that As(+3) can act as a tumor promoter during the regeneration of the bladder urothelium. The present in vitro studies suggest that As(+3)-induced cytotoxicity could set the stage for tissue repair due to its own inherent toxicity to normal urothelium, and then subsequently act as a tumor promoter during the regeneration process through the stimulation of the regrowth of cells that have gained increased resistance to As(+3).
Somji
Seema
S
Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58202, USA. ssomji@medicine.nodak.edu
Zhou
Xu Dong
XD
Garrett
Scott H
SH
Sens
Mary Ann
MA
Sens
Donald A
DA
D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000633:toxicity*; D002104:Cadmium / Q000633:toxicity*; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008668:Metallothionein / Q000378:metabolism; D009336:Necrosis; D019459:Urothelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D018053:Arsenites; D002104:Cadmium; D008668:Metallothionein; D007770:L-Lactate Dehydrogenase; D020169:Caspases; C015001:arsenite