title: Resensitization of HTLV-1 infected T cells towards apoptosis by rocaglamide involves inhibition of protein translation
creator: Bleumink, Marc
subject: 570
subject: 570 Life sciences
description: Human T cell Leukemia Virus Type 1 (HTLV-1) is a retrovirus, associated with several diseases including Adult T-cell Leukemia/Lymphoma (ATL). Because of apoptosis resistance treatment provides only limited benefits for ATL. CD95/CD95L-mediated apoptosis is an important mechanism of T cell homeostasis. We have previously shown that HTLV-1 infected T cells are more resistant to CD95L-induced apoptosis as compared to non HTLV-1 infected T cells. In this study we showed that HTLV-1 infected T cells are also resistant towards TRAIL, which suggests a general mechanism of resistance towards death receptor-mediated apoptosis.  The basis of apoptotic resistance in HTLV-1 infected T cells was suggested to be due to the elevated expression of several anti-apoptotic proteins involved in modulation of the intrinsic cell death pathway. Recently our group further found that apoptosis is also blocked within the extrinsic cell death pathway by high c-FLIP expression. C-FLIP is an anti-apoptotic protein that blocks death receptor-mediated apoptosis at the DISC level. To overcome resistance, we have treated HTLV-1 infected T cells with CD95L or TRAIL in combination with an herbal compound, Rocaglamide, derived from a Traditional Chinese Medicinal plant (TCM). We showed that one of the Rocaglamide derivatives tested, Roc-AR, sensitizes HTLV-1 infected T cells towards CD95L- and TRAIL-mediated apoptosis via down-regulation of c-FLIP expression at the translational level. Further investigation of the molecular mechanisms by which Roc-AR suppresses c-FLIP translation, revealed a mechanism different from other known translation inhibitors. Roc-AR strongly inhibits the Ras pathway leading to the inhibition of Mnk-1, a protein kinase essential for the activation of the translation initiation factor 4E (eIF4E). Thus, blocking activation of eIF4E by Roc-AR leads to inhibition of cap-dependent eukaryotic translation at the initiation stage. Most importantly, Roc-AR does not sensitize normal peripheral blood T cells to CD95L-and TRAIL-induced apoptosis. Our study raises the possibility to develop Roc-AR as CD95L or TRAIL adjuvant for treatment of ATL and other types of T-cell tumors.  
date: 2007
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/7690/1/Dissertation_M._Bleumink.pdf
identifier: DOI:10.11588/heidok.00007690
identifier: urn:nbn:de:bsz:16-opus-76904
identifier:   Bleumink, Marc  (2007) Resensitization of HTLV-1 infected T cells towards apoptosis by rocaglamide involves inhibition of protein translation.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/7690/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng