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1 PublicationDouble targeting of Survivin and XIAP radiosensitizes 3D grown human colorectal tumor cells and decreases migration.
Hehlgans, S.; Petraki, C.; Reichert, S.; Cordes, N.; Rödel, C.; Rödel, F.
Abstract
BACKGROUND AND PURPOSE:
In the present study, we aimed to investigate the effect of single and double knockdown of the inhibitor of apoptosis proteins (IAP) Survivin and X-linked IAP (XIAP) on three-dimensional (3D) clonogenic survival, migration capacity and underlying signaling pathways.
MATERIALS AND METHODS:
Colorectal cancer cell lines (HCT-15, SW48, SW480, SW620) were subjected to siRNA-mediated single or Survivin/XIAP double knockdown followed by 3D colony forming assays, cell cycle analysis, Caspase activity assays, migration assays, matrigel transmigration assays and Western blotting (Survivin, XIAP, Focal adhesion kinase (FAK), p-FAK Y397, Akt1, p-Akt1 S473, Extracellular signal-regulated kinase (ERK1/2), p-ERK1/2 T202/Y204, Glycogen synthase kinase (GSK)3β, p-GSK3β S9, nuclear factor (NF)-κB p65).
RESULTS:
While basal cell survival was altered cell line-dependently, Survivin or XIAP single and Survivin/XIAP double knockdown enhanced cellular radiosensitivity of all tested cancer cell lines grown in 3D. Particularly double knockdown conditions revealed accumulation of cells in G2/M, increased subG1 fraction, elevated Caspase 3/7 activity, and reduced migration. Intracellular signaling showed dephosphorylation of FAK and Akt1 upon Survivin and/or Survivin/XIAP silencing.
CONCLUSIONS:
Our results strengthen the notion of Survivin and XIAP to act as radiation resistance factors and further indicate that these apoptosis-regulating proteins are also functioning in cell cycling and cell migration.
Keywords: Colorectal cancer; Invasion; Ionizing radiation; Migration; Survivin; Three-dimensional cell culture; XIAP
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Radiotherapy and Oncology 108(2013)1, 32-39
DOI: 10.1016/j.radonc.2013.06.006
Cited 29 times in Scopus
Permalink: https://www.hzdr.de/publications/Publ-19904