Canagliflozin Inhibits Glioblastoma Growth and Proliferation by Activating AMPK
Canagliflozin Inhibits Glioblastoma Growth and Proliferation by Activating AMPK
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Canagliflozin 通过激活 AMPK 抑制胶质母细胞瘤生长和增殖
DOI：
10.1007/s10571-022-01221-8
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发表时间：
2022
影响因子：
4
通讯作者：
Hara Hideaki
中科院分区：
文献类型：
--
作者：
Shoda Kenji;Tsuji Shohei;Nakamura Shinsuke;Egashira Yusuke;Enomoto Yukiko;Nakayama Noriyuki;Shimazawa Masamitsu;Iwama Toru;Hara Hideaki
钠-葡萄糖转运蛋白2（SGLT 2）抑制剂是影响SGLT 2的降糖药物。最近的研究表明，各种癌症表达SGLT 2，SGLT 2抑制剂减弱肿瘤增殖。我们评价了卡格列净（一种SGLT 2抑制剂）对胶质母细胞瘤（GBM）的抗肿瘤活性。使用三种GBM细胞系，U251 MG（人）、U87 MG（人）和GL 261（鼠）。我们通过免疫印迹、细胞使用、细胞活力测定和卡格列净葡萄糖摄取测定评估GBM的SGLT 2表达。然后，我们评估磷酸化的AMP活化蛋白激酶（AMPK），p70 S6激酶，和S6核糖体蛋白的免疫印迹。在这些试验中使用了浓度为5、10、20和40 μM的卡格列净。我们还使用具有SGLT 2的siRNA敲低的U251 MG评估了细胞活力和免疫印迹。此外，我们将小鼠分为媒介物组和卡格列净组。卡格列净组从GBM移植后第3天开始口服给予100 mg/kg卡格列净，持续10天。取出脑，并使用切片评估肿瘤体积。SGLT 2在GBM细胞和GBM移植小鼠中均有表达。40 μM卡格列净给药可显著抑制细胞增殖和细胞葡萄糖摄取。此外，40 μM卡格列净显著增加AMPK的磷酸化，并抑制p70 S6激酶和S6核糖体蛋白的磷酸化。使用siRNA SGLT 2获得了细胞活力测定和免疫印迹的类似结果。此外，尽管卡格列净组的效果不如体外，但它显著抑制了GBM移植小鼠的肿瘤生长。这表明卡格列净可用作GBM的潜在治疗。
Sodium-glucose transporter 2 (SGLT2) inhibitors are antidiabetic drugs affecting SGLT2. Recent studies have shown various cancers expressing SGLT2, and SGLT2 inhibitors attenuating tumor proliferation. We evaluated the antitumor activities of canagliflozin, a SGLT2 inhibitor, on glioblastoma (GBM). Three GBM cell lines, U251MG (human), U87MG (human), and GL261 (murine), were used. We assessed the expression of SGLT2 of GBM through immunoblotting, specimen-use, cell viability assays, and glucose uptake assay with canagliflozin. Then, we assessed phosphorylation of AMP-activated protein kinase (AMPK), p70 S6 kinase, and S6 ribosomal protein by immunoblotting. Concentrations of 5, 10, 20, and 40 μM canagliflozin were used in these tests. We also evaluated cell viability and immunoblotting using U251MG with siRNA knockdown of SGLT2. Furthermore, we divided the mice into vehicle group and canagliflozin group. The canagliflozin group was administrated with 100 mg/kg of canagliflozin orally for 10 days starting from the third days post-GBM transplant. The brains were removed and the tumor volume was evaluated using sections. SGLT2 was expressed in GBM cell and GBM allograft mouse. Canagliflozin administration at 40 μM significantly inhibited cell proliferation and glucose uptake into the cell. Additionally, canagliflozin at 40 μM significantly increased the phosphorylation of AMPK and suppressed that of p70 S6 kinase and S6 ribosomal protein. Similar results of cell viability assays and immunoblotting were obtained using siRNA SGLT2. Furthermore, although less effective than in vitro, the canagliflozin group significantly suppressed tumor growth in GBM-transplanted mice. This suggests that canagliflozin can be used as a potential treatment for GBM.