Chandrika Goparaju, Natesh Kumar, Ranade Deepak, Chugh Ashish, Shastry Padma
National Centre for Cell Science (NCCS), Savitribai Phule Pune University Campus, Pune, India.
Department of Neurosurgery, D.Y. Patil Medical College, Pune, India.
Sci Rep. 2016 Mar 4;6:22455. doi: 10.1038/srep22455.
Glioblastoma (GBM) is the most aggressive type of brain tumors in adults with survival period <1.5 years of patients. The role of mTOR pathway is documented in invasion and migration, the features associated with aggressive phenotype in human GBM. However, most of the preclinical and clinical studies with mTOR inhibitors are focused on antiproliferative and cytotoxic activity in GBM. In this study, we demonstrate that mTOR inhibitors-rapamycin (RAP), temisirolimus (TEM), torin-1 (TOR) and PP242 suppress invasion and migration induced by Tumor Necrosis Factor-α (TNFα) and tumor promoter, Phorbol 12-myristate 13-acetate (PMA) and also reduce the expression of the TNFα and IL1β suggesting their potential to regulate factors in microenvironment that support tumor progression. The mTOR inhibitors significantly decreased MMP-2 and MMP-9 mRNA, protein and activity that was enhanced by TNFα and PMA. The effect was mediated through reduction of Protein kinase C alpha (PKC-α) activity and downregulation of NFκB. TNFα- induced transcripts of NFκB targets -VEGF, pentraxin-3, cathepsin-B and paxillin, crucial in invasion were restored to basal level by these inhibitors. With limited therapeutic interventions currently available for GBM, our findings are significant and suggest that mTOR inhibitors may be explored as anti-invasive drugs for GBM treatment.
胶质母细胞瘤（GBM）是成人中最具侵袭性的脑肿瘤类型，患者生存期<1.5年。mTOR通路在侵袭和迁移中的作用已有文献记载，这些特征与人类GBM的侵袭性表型相关。然而，大多数使用mTOR抑制剂的临床前和临床研究都集中在GBM的抗增殖和细胞毒性活性上。在本研究中，我们证明mTOR抑制剂——雷帕霉素（RAP）、替西罗莫司（TEM）、托林-1（TOR）和PP242可抑制肿瘤坏死因子-α（TNFα）和肿瘤启动子佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）诱导的侵袭和迁移，还可降低TNFα和IL1β的表达，表明它们有调节支持肿瘤进展的微环境中因子的潜力。mTOR抑制剂显著降低了TNFα和PMA增强的基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）的mRNA、蛋白水平及活性。该作用是通过降低蛋白激酶Cα（PKC-α）活性和下调核因子κB（NFκB）介导的。这些抑制剂将TNFα诱导的NFκB靶标——血管内皮生长因子（VEGF）、五聚素-3、组织蛋白酶-B和桩蛋白的转录本恢复到基础水平，这些转录本在侵袭过程中至关重要。鉴于目前GBM的治疗干预措施有限，我们的研究结果意义重大，表明mTOR抑制剂可作为GBM治疗的抗侵袭药物进行探索。
