ABSTRACT
New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10ß1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10ß1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody-drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10ß1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10ß1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.
ABSTRACT
Nemo-like kinase (NLK), a proline-directed serine/threonine kinase regulated by phosphorylation, can be localized in the cytosol or in the nucleus. Whether the localization of NLK can affect cell survival or cell apoptosis is yet to be disclosed. In the present study we found that NLK was mainly localized in the nuclei of breast cancer cells, in contrast to a cytosolic localization in non-cancerous breast epithelial cells. The nuclear localization of NLK was mediated through direct interaction with Heat shock protein 27 (HSP27) which further protected cancer cells from apoptosis. The present study provides evidence of a novel mechanism by which HSP27 recognizes NLK in the breast cancer cells and prevents NLK-mediated cell apoptosis.