Sun Peng, Liu Fude, Huo Kang, Wang Jianyi, Cheng Yawen, Shang Suhang, Ma Wenlong, Yu Jia, Han Jianfeng
Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Oncol Lett. 2025 Jan 7;29(3):127. doi: 10.3892/ol.2025.14875. eCollection 2025 Mar.
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 G 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.
脂联素（ADN）通过调节DNA合成、细胞凋亡和细胞周期参与胶质母细胞瘤的病理过程和进展。本研究旨在进一步探讨ADN对胶质母细胞瘤中替莫唑胺（TMZ）耐药性的影响及其潜在作用机制。用不同浓度的ADN和TMZ处理胶质母细胞瘤细胞系（U251和U87-MG细胞）；随后，选择3.0μg/ml ADN和1.0 mM TMZ作为实验条件的最佳浓度。将LY294002（一种PI3K抑制剂）添加到经ADN或ADN + TMZ处理的胶质母细胞瘤细胞系中。使用细胞计数试剂盒-8检测法测定细胞生长速率，使用膜联蛋白V/碘化丙啶和细胞周期检测法评估凋亡率和细胞周期，通过蛋白质免疫印迹法测定p-Akt（Thr308）、p-Akt（Ser473）、Akt、p-mTOR、c-半胱天冬酶3、半胱天冬酶3、Bax、细胞周期蛋白B1和细胞周期蛋白D1的表达。脂联素受体（ADIPOR）1和ADIPOR2在胶质母细胞瘤细胞系中表达。ADN以浓度和时间依赖性方式提高胶质母细胞瘤细胞系的生长速率。ADN抑制胶质母细胞瘤细胞系凋亡并促进细胞周期进程。值得注意的是，ADN激活了Akt/mTOR通路，添加LY294002可逆转ADN的作用，表明ADN通过激活Akt/mTOR通路抑制胶质母细胞瘤细胞系凋亡并促进细胞周期进程。值得注意的是，TMZ抑制胶质母细胞瘤细胞系生长、促进凋亡并增加G期细胞周期阻滞。然而，添加ADN可逆转TMZ对胶质母细胞瘤细胞系的作用，表明ADN诱导TMZ耐药。明显的是，LY294002进一步减弱了ADN介导的TMZ耐药性，提示ADN通过激活Akt/mTOR通路诱导胶质母细胞瘤细胞系产生TMZ耐药。总之，ADN通过激活Akt/mTOR通路促进细胞周期进程、抑制细胞凋亡并诱导胶质母细胞瘤产生TMZ耐药。
