Targeting integrin α2 as potential strategy for radiochemosensitization of glioblastoma

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

Abstract

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 the 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 the 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.

Details

OriginalspracheEnglisch
Seiten (von - bis)648-661
Seitenumfang14
FachzeitschriftNeuro-oncology
Jahrgang25
Ausgabenummer4
PublikationsstatusVeröffentlicht - 6 Apr. 2023
Peer-Review-StatusJa

Externe IDs

PubMedCentral PMC10076950
Scopus 85154592804
ORCID /0000-0002-5381-0547/work/146642809
ORCID /0000-0001-5684-629X/work/146646164
Mendeley d035e3b2-a14f-3ac7-b148-70064c34f80e

Schlagworte

Forschungsprofillinien der TU Dresden

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Humans, Animals, Mice, Glioblastoma/pathology, Integrin alpha2/therapeutic use, Drug Resistance, Neoplasm, Brain Neoplasms/pathology, Temozolomide/therapeutic use, Cell Line, Tumor, Xenograft Model Antitumor Assays, Antineoplastic Agents, Alkylating/therapeutic use, ATF1, integrin α2, radiochemoresistance, ERK1, glioblastoma