Adiponectin facilitates the cell cycle, inhibits cell apoptosis and induces temozolomide resistance in glioblastoma via the Akt/mTOR pathway

Abstract

Adiponectin (ADN) regulates DNA synthesis, cell apoptosis and cell cycle to participate in the pathology and progression of glioblastoma. The present study aimed to further explore the effect of ADN on temozolomide (TMZ) resistance in glioblastoma and the underlying mechanism of action. Glioblastoma cell lines (U251 and U87-MG cells) were treated with ADN and TMZ at different concentrations; subsequently, 3.0 µg/ml ADN and 1.0 mM TMZ were selected as the optimal concentrations for the experimental conditions. LY294002 (a PI3K inhibitor) was added to ADN or ADN + TMZ-treated glioblastoma cell lines. Cell growth rate was determined using the Cell Counting Kit-8 assay, the apoptotic rate and cell cycle were evaluated using Annexin V/propidium iodide and cell cycle assays, and p-Akt (Thr308), p-Akt (Ser473), Akt, p-mTOR, c-caspase 3, caspase 3, Bax, cyclin B1 and cyclin D1 expression was determined by western blotting. Adiponectin receptor (ADIPOR) 1 and ADIPOR2 were expressed in glioblastoma cell lines. The glioblastoma cell line growth rate was increased by ADN in a concentration- and time-dependent manner. ADN inhibited glioblastoma cell line apoptosis and facilitated cell cycle. Of note, ADN activated the Akt/mTOR pathway and the addition of LY294002 reversed the effect of ADN, indicating that ADN activated the Akt/mTOR pathway to suppress apoptosis and promote cell cycle in glioblastoma cell lines. Notably, TMZ inhibited glioblastoma cell line growth, promoted apoptosis and increased G₂ phase cell cycle arrest. However, the addition of ADN reversed the effect of TMZ in glioblastoma cell lines, disclosing that ADN induced TMZ resistance. Markedly, ADN-mediated TMZ resistance was further attenuated by LY294002, suggesting that ADN activated the Akt/mTOR pathway to induce TMZ resistance in glioblastoma cell lines. In conclusion, ADN activated the Akt/mTOR pathway to facilitate cell cycle, inhibit cell apoptosis and induce TMZ resistance in glioblastoma.

Keywords: Akt/mTOR pathway; adiponectin; cell cycle and apoptosis; glioblastoma; temozolomide resistance.