Integrin-linked kinase: dispensable for radiation survival of three-dimensionally cultured fibroblasts.
OBJECTIVE
Cancer treatment by conventional radiotherapy is limited by normal tissue side-effects. Fibroblasts as "non-target" stromal cell type are considered as strong promoter of tumor growth and for developing a therapy resistant phenotype. Regarding application of novel molecular therapeutics combined with radiotherapy, evaluation of a specific targeted molecule in both tumor and normal cells is mandatory for efficacy and tolerability assessment. Previous work showed integrin-linked kinase (ILK), a mediator of beta-integrin signals and putative phosphorylator of AKT, as potent anti-survival regulator in human cancer cell lines.


METHODS
To evaluate the role of ILK in normal fibroblast survival, ILK-wild-type (ILK(fl/fl)), ILK(-/-) and ILK(N-terminal) and ILK(C-terminal) domain expressing fibroblasts were irradiated with X-rays on different substrata or in three-dimensional laminin-rich extracellular matrix (lrECM).


RESULTS
On control substrata, ILK-deficient and ILK-mutant fibroblasts showed significant increase in radiation survival relative to ILK-wild-type cells. This effect was compensated by growth on ECM proteins and in 3D lrECM. ILK regulated AKT activity in a phosphatidylinositol-3 kinase (PI3K)-dependent manner. Upon PI3K inhibition, only ILK-wild-type fibroblasts showed significant radiosensitization.


CONCLUSIONS
These findings obtained in 3D cell cultures suggest ILK to be dispensable for the radiation survival response of normal fibroblasts. However, targeting the PI3K/AKT signaling axis pharmacologically might be critical for survival of normal fibroblasts exposed to ionizing radiation.
Hehlgans
Stephanie
S
OncoRay - Center for Radiation Research in Oncology, Dresden University of Technology, Fetscherstrasse, Germany.
Eke
Iris
I
Deuse
Yvonne
Y
Cordes
Nils
N
D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000528:radiation effects*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011836:Radiation Tolerance; D014965:X-Rays / Q000009:adverse effects*; D000099200:Scaffold Protein ILK
D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK