Publikationsrepositorium - Helmholtz-Zentrum Dresden-Rossendorf

Background. Glioblastoma (GBM) is a fast-growing primary brain tumor characterized by high
invasiveness and resistance. This results in poor patient survival. Resistance is caused by
many factors, including cell-extracellular matrix (ECM) interactions. Here, we addressed the
role of adhesion protein integrin α2, which we identified in a high-throughput screen for novel
potential targets in GBM cells treated with standard therapy consisting of temozolomide (TMZ)
and radiation.
Methods. In our study, we used a range of primary/stem-like and established GBM cell models
in vitro and in vivo. To identify regulatory mechanisms, we employed high-throughput kinome
profiling, Western blotting, immunofluorescence staining, reporter and activity assays.
Results. Our data showed that integrin α2 is overexpressed in GBM compared to normal brain
and, that its deletion causes radiochemosensitization. Similarly, invasion and adhesion were
significantly reduced in TMZ-irradiated GBM cell models. Furthermore, we found that integrin
α2-knockdown impairs proliferation of GBM cells without affecting DNA damage repair. At the
mechanistic level, we found that integrin α2 affects the activity of activating transcription factor
1 (ATF1) and modulates the expression of extracellular signal-regulated kinase 1 (ERK1)
regulated by extracellular signals. Finally, we demonstrated that integrin α2-deficiency inhibits
tumor growth and thereby prolongs survival of mice with orthotopically growing GBM
xenografts.
Conclusions. Taken together our data suggest that integrin α2 may be a promising target to
overcome GBM resistance to radio- and chemotherapy. Thus, it would be worth evaluating
how efficient and safe the adjuvant use of integrin α2 inhibitors is to standard
radio(chemo)therapy in GBM.