| Abstract |
In the present work the expression of the TRAIL system in human renal
carcinoma cell lines was investigated. For the first time two previously
unknown alternative TRAIL splice variants could be identified and
characterized. In the TRAIL beta isoform, the processing of the exon 3
leads to the translation of a truncated 98 amino acid protein with loss of
the extracellular domain. The additional processing of exon 2 leads to the
generation of the TRAIL-gamma variant with 52 amino acids and almost
complete truncation of the extracellular binding domains. Due to the loss
of the extracellular domain of these TRAIL variants, which appears
essential for signal induction by receptor binding, an apoptotic effect is
very questionable. While TRAIL alpha and beta have a cytoplasmic
localization. In addition, a previously unidentified splice variant of the
type 4 TRAIL receptor was discovered. This form has truncation of the
cysteine-rich domain 1, which is important for the ligand-receptor
interaction. This may lead to a changed affinity of the ligand-receptor
complex. As has already been shown, rhTRAIL induces apoptotic cell death
in human renal carcinoma cell lines. Furthermore, a primary TRAIL
sensitivity could be enhanced by co-administration of the topoisomerase
inhibitor topotecan (hycamtin). The mechanisms responsible for this were
not yet known. For this reason, the role of the IAP family was
specifically examined in this context. A significant decrease in the
expression of IAP-2 after topotecan administration was observed. Survivin,
another member of the IAP family, has recently gained particular attention
through its selective re-expression in malignant transformed tissue. A
significant correlation was found between poor prognosis of different
types of malignant tumors and increased survivin expression. After
identification of the splice variants survivin-deltaEx3 and -2B with
different anti-apoptotic potential, the in vivo expression of survivin
variants in the gastric and renal cell carcinomas was investigated. In the
gastric and renal cell carcinomas, a significant decrease in the
expression of proapototic survivin-2B was observed in advanced tumor
stages. The more aggressive clear cell renal cell carcinomas showed a
significantly higher expression of survivin variants than
chromophilic/papillary differentiated renal cell carcinomas. The decrease
of proapototic survivin-2B could reduce the willingness to apoptotic cell
death during tumor progression.
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