Stem cells are resistant to TRAIL receptor-mediated apoptosis.
New therapeutic approaches aim to eradicate tumours by expression of tumouricidal proteins in the tumour stroma. One such anti-neoplastic protein is tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) because it induces apoptosis in cancerous cells, but not in non-transformed cells. Stem cells can migrate to, survive and proliferate in tumours. We examined the suitability of bone marrow-derived adult mesenchymal stem cells (bmMSC), foetal-MSC and umbilical cord matrix stem cells (Wharton's Jelly MSCs) as TRAIL-delivery vehicles. Although all MSC types expressed DR4 and/or DR5, none of them were sensitive to TRAIL-induced apoptosis. Selective activation of DR4 or DR5 with agonistic antibodies or DR5-selective TRAIL-mutant (D269H/E195R) revealed that the TRAIL receptors are inactive in MSCs. In fMSC DR5 was not fully inactivated, its activity however was minimal in comparison to the colon carcinoma cell, Colo205. The intracellular components of the TRAIL-apoptotic pathway, such as pro-caspase-8 and -9 were also expressed at very low; almost undetectable levels in all three MSC types. In conclusion, the MSC species examined are resistant to TRAIL and thus can be suitable tools for TRAIL delivery to tumours.
Szegezdi
Eva
E
Department of Biochemistry and National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland.
O'Reilly
Aoife
A
Davy
Yeung
Y
Vawda
Reaz
R
Taylor
Deanna L
DL
Murphy
Mary
M
Samali
Afshin
A
Mehmet
Huseyin
H
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand