Targeting integrin α2 as potential strategy for radiochemosensitization of glioblastoma

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 alpha 2, 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 alpha 2 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 alpha 2-knockdown impairs the proliferation of GBM cells without affecting DNA damage repair. At the mechanistic level, we found that integrin alpha 2 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 alpha 2-deficiency inhibits tumor growth and thereby prolongs the survival of mice with orthotopically growing GBM xenografts. Conclusions Taken together our data suggest that integrin alpha 2 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 alpha 2 inhibitors is to standard radio(chemo)therapy in GBM.

Automated summary

Integrin alpha 2 is overexpressed in GBM compared to normal brain, and its deletion causes radiochemosensitization and reduces invasion and adhesion in GBM cells post TMZ-irradiation. Knockdown of integrin alpha 2 impairs cell proliferation without affecting DNA damage repair, and it affects ATF1 activity and modulates ERK1 expression regulated by external signals. Integrin alpha 2-deficiency inhibits tumor growth and extends survival in mice with orthotopically growing GBM xenografts.