期刊
ONCOTARGET
卷 8, 期 17, 页码 27754-27771出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10897
关键词
malignant gliomas; integrin alpha V beta 3 silencing; temozolomide; homologous recombination repair; Rad51
资金
- grants of the German Academic Exchange Service-DAAD (Federal Ministry for Education and Research-BMBF) [57059522]
- German Cancer Aid (Mildred Scheel Foundation) [AZ-111404]
- grant of the Croatian Ministry of Science, Education and Sports [098-0982913-2850]
- Croatian Science Foundation [IP-11-2013-2465]
Integrins have been suggested as possible targets in anticancer therapy. Here we show that knockdown of integrins alpha V beta 3, alpha V beta 5, alpha 3 beta 1 and alpha 4 beta 1 and pharmacological inhibition using a cyclo-RGD integrin alpha V beta 3/alpha V beta 5 antagonist sensitized multiple high-grade glioma cell lines to temozolomide (TMZ)-induced cytotoxicity. The greatest effect was observed in LN229 cells upon integrin beta 3 silencing, which led to inhibition of the FAK/Src/Akt/NF.B signaling pathway and increased formation of gamma H2AX foci. The integrin beta 3 knockdown led to the proteasomal degradation of Rad51, reduction of Rad51 foci and reduced repair of TMZ-induced DNA double-strand breaks by impairing homologous recombination efficiency. The down-regulation of beta 3 in Rad51 knockdown (LN229-Rad51kd) cells neither further sensitized them to TMZ nor increased the number of gamma H2AX foci, confirming causality between beta 3 silencing and Rad51 reduction. RIP1 was found cleaved and I kappa Ba significantly less degraded in beta 3-silenced/TMZ-exposed cells, indicating inactivation of NF kappa B signaling. The anti-apoptotic proteins Bcl-xL, survivin and XIAP were proteasomally degraded and caspase-3/-2 cleaved. Increased H2AX phosphorylation, caspase-3 cleavage, reduced Rad51 and RIP1 expression, as well as sustained I kappa Ba expression were also observed in mouse glioma xenografts treated with the cyclo-RGD inhibitor and TMZ, confirming the molecular mechanism in vivo. Our data indicates that beta 3 silencing in glioma cells represents a promising strategy to sensitize high-grade gliomas to TMZ therapy.
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