Targeting MAGI2‐AS3‐modulated Akt‐dependent ATP‐binding cassette transporters as a possible strategy to reverse temozolomide resistance in temozolomide‐resistant glioblastoma cells

Abstract

AbstractDrug resistance is a major impediment to the successful treatment of glioma. This study aimed to elucidate the effects and mechanisms of the long noncoding RNA membrane‐associated guanylate kinase inverted‐2 antisense RNA 3 (MAGI2‐AS3) on temozolomide (TMZ) resistance in glioma cells. MAGI2‐AS3 expression in TMZ‐resistant glioblastoma (GBM) cells was analyzed using the Gene Expression Omnibus data set GSE113510 and quantitative real‐time PCR (qRT‐PCR). Cell viability and TMZ half‐maximal inhibitory concentration values were determined using the MTT assay. Apoptosis and cell cycle distribution were evaluated using flow cytometry. The expression of multidrug resistance 1 (MDR1), ATP‐binding cassette superfamily G member 2 (ABCG2), protein kinase B (Akt), and phosphorylated Akt was detected using qRT‐PCR and/or western blot analysis. MAGI2‐AS3 was expressed at low levels in TMZ‐resistant GBM cells relative to that in their parental cells. MAGI2‐AS3 re‐expression alleviated TMZ resistance in TMZ‐resistant GBM cells. MAGI2‐AS3 overexpression also accelerated TMZ‐induced apoptosis and G2/M phase arrest. Mechanistically, MAGI2‐AS3 overexpression reduced MDR1 and ABCG2 expression and inhibited the Akt pathway, whereas Akt overexpression abrogated the reduction in MDR1 and ABCG2 expression induced by MAGI2‐AS3. Moreover, activation of the Akt pathway inhibited the effects of MAGI2‐AS3 on TMZ resistance. MAGI2‐AS3 inhibited tumor growth and enhanced the suppressive effect of TMZ on glioma tumorigenesis in vivo. In conclusion, MAGI2‐AS3 reverses TMZ resistance in glioma cells by inactivating the Akt pathway.