![[feed]](/style/images/feed-icon-14x14.png){kind=icon}
![[img]](http://edoc.mdc-berlin.de/style/images/fileicons/application_pdf.png) |
PDF
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
2MB |
| Item Type: | Article |
|---|---|
| Title: | Targeted therapy of the XIAP/proteasome pathway overcomes TRAIL-resistance in carcinoma by switching apoptosis signaling to a Bax/Bak-independent 'type I' mode |
| Creators Name: | Gillissen, B. and Richter, A. and Richter, A. and Overkamp, T. and Essmann, F. and Hemmati, P.G. and Preissner, R. and Belka, C. and Daniel, P.T. |
| Abstract: | TRAIL is a promising anticancer agent, capable of inducing apoptosis in a wide range of treatment-resistant tumor cells. In 'type II' cells, the death signal triggered by TRAIL requires amplification via the mitochondrial apoptosis pathway. Consequently, deregulation of the intrinsic apoptosis-signaling pathway, for example, by loss of Bax and Bak, confers TRAIL-resistance and limits its application. Here, we show that despite resistance of Bax/Bak double-deficient cells, TRAIL-treatment resulted in caspase-8 activation and complete processing of the caspase-3 proenzymes. However, active caspase-3 was degraded by the proteasome and not detectable unless the XIAP/proteasome pathway was inhibited. Direct or indirect inhibition of XIAP by RNAi, Mithramycin A or by the SMAC mimetic LBW-242 as well as inhibition of the proteasome by Bortezomib overcomes TRAIL-resistance of Bax/Bak double-deficient tumor cells. Moreover, activation and stabilization of caspase-3 becomes independent of mitochondrial death signaling, demonstrating that inhibition of the XIAP/proteasome pathway overcomes resistance by converting 'type II' to 'type I' cells. Our results further demonstrate that the E3 ubiquitin ligase XIAP is a gatekeeper critical for the 'type II' phenotype. Pharmacological manipulation of XIAP therefore is a promising strategy to sensitize cells for TRAIL and to overcome TRAIL-resistance in case of central defects in the intrinsic apoptosis-signaling pathway. |
| Keywords: | TRAIL, XIAP, SMAC, Bax, Bak, Apoptosis |
| Source: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Publisher: | Nature Publishing Group |
| Volume: | 4 |
| Page Range: | e643 |
| Date: | 23 May 2013 |
| Official Publication: | https://doi.org/10.1038/cddis.2013.67 |
| PubMed: | View item in PubMed |
Repository Staff Only: item control page
Download Statistics
Download Statistics
