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том 9 издание 9 страницы e107165

EGFR-Targeted TRAIL and a Smac Mimetic Synergize to Overcome Apoptosis Resistance in KRAS Mutant Colorectal Cancer Cells

Тип публикацииJournal Article
Дата публикации2014-09-08
scimago Q1
wos Q2
БС1
SJR0.803
CiteScore5.4
Impact factor2.6
ISSN19326203
Multidisciplinary
Краткое описание
TRAIL is a death receptor ligand that induces cell death preferentially in tumor cells. Recombinant soluble TRAIL, however, performs poorly as an anti-cancer therapeutic because oligomerization is required for potent biological activity. We previously generated a diabody format of tumor-targeted TRAIL termed DbαEGFR-scTRAIL, comprising single-stranded TRAIL molecules (scTRAIL) and the variable domains of a humanized variant of the EGFR blocking antibody Cetuximab. Here we define the bioactivity of DbαEGFR-scTRAIL with regard to both EGFR inhibition and TRAIL receptor activation in 3D cultures of Caco-2 colorectal cancer cells, which express wild-type K-Ras. Compared with conventional 2D cultures, Caco-2 cells displayed strongly enhanced sensitivity toward DbαEGFR-scTRAIL in these 3D cultures. We show that the antibody moiety of DbαEGFR-scTRAIL not only efficiently competed with ligand-induced EGFR function, but also determined the apoptotic response by specifically directing DbαEGFR-scTRAIL to EGFR-positive cells. To address how aberrantly activated K-Ras, which leads to Cetuximab resistance, affects DbαEGFR-scTRAIL sensitivity, we generated stable Caco-2tet cells inducibly expressing oncogenic K-RasG12V. In the presence of doxycycline, these cells showed increased resistance to DbαEGFR-scTRAIL, associated with the elevated expression of the anti-apoptotic proteins cIAP2, Bcl-xL and FlipS. Co-treatment of cells with the Smac mimetic SM83 restored the DbαEGFR-scTRAIL-induced apoptotic response. Importantly, this synergy between DbαEGFR-scTRAIL and SM83 also translated to 3D cultures of oncogenic K-Ras expressing HCT-116 and LoVo colorectal cancer cells. Our findings thus support the notion that DbαEGFR-scTRAIL therapy in combination with apoptosis-sensitizing agents may be promising for the treatment of EGFR-positive colorectal cancers, independently of their KRAS status.
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ГОСТ |
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Möller Y. et al. EGFR-Targeted TRAIL and a Smac Mimetic Synergize to Overcome Apoptosis Resistance in KRAS Mutant Colorectal Cancer Cells // PLoS ONE. 2014. Vol. 9. No. 9. p. e107165.
ГОСТ со всеми авторами (до 50) Скопировать
Möller Y., Siegemund M., Beyes S., Herr R., Lecis D., Delia D., Kontermann R., Brummer T., Pfizenmaier K., Olayioye M. A. EGFR-Targeted TRAIL and a Smac Mimetic Synergize to Overcome Apoptosis Resistance in KRAS Mutant Colorectal Cancer Cells // PLoS ONE. 2014. Vol. 9. No. 9. p. e107165.
RIS |
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TY - JOUR
DO - 10.1371/journal.pone.0107165
UR - https://doi.org/10.1371/journal.pone.0107165
TI - EGFR-Targeted TRAIL and a Smac Mimetic Synergize to Overcome Apoptosis Resistance in KRAS Mutant Colorectal Cancer Cells
T2 - PLoS ONE
AU - Möller, Yvonne
AU - Siegemund, Martin
AU - Beyes, Sven
AU - Herr, Ricarda
AU - Lecis, Daniele
AU - Delia, Domenico
AU - Kontermann, Roland
AU - Brummer, Tilman
AU - Pfizenmaier, Klaus
AU - Olayioye, Monilola A.
PY - 2014
DA - 2014/09/08
PB - Public Library of Science (PLoS)
SP - e107165
IS - 9
VL - 9
PMID - 25198428
SN - 1932-6203
ER -
BibTex |
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BibTex (до 50 авторов) Скопировать
@article{2014_Möller,
author = {Yvonne Möller and Martin Siegemund and Sven Beyes and Ricarda Herr and Daniele Lecis and Domenico Delia and Roland Kontermann and Tilman Brummer and Klaus Pfizenmaier and Monilola A. Olayioye},
title = {EGFR-Targeted TRAIL and a Smac Mimetic Synergize to Overcome Apoptosis Resistance in KRAS Mutant Colorectal Cancer Cells},
journal = {PLoS ONE},
year = {2014},
volume = {9},
publisher = {Public Library of Science (PLoS)},
month = {sep},
url = {https://doi.org/10.1371/journal.pone.0107165},
number = {9},
pages = {e107165},
doi = {10.1371/journal.pone.0107165}
}
MLA
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Möller, Yvonne, et al. “EGFR-Targeted TRAIL and a Smac Mimetic Synergize to Overcome Apoptosis Resistance in KRAS Mutant Colorectal Cancer Cells.” PLoS ONE, vol. 9, no. 9, Sep. 2014, p. e107165. https://doi.org/10.1371/journal.pone.0107165.