Research Paper Volume 9, Issue 4 pp 1233—1247

Aspirin inhibits the SHH/GLI1 signaling pathway and sensitizes malignant glioma cells to temozolomide therapy

Jianguang Ming 1, 2, *, , Bo Sun 1, 2, *, , Ziwei Li 1, 2, , Lin Lin 1, 2, , Xiangqi Meng 1, 2, , Bo Han 1, 2, , Ruijia Wang 1, 2, , Pengfei Wu 1, 2, , Jianlong Li 1, 2, , Jinquan Cai 1, 2, 3, , Chuanlu Jiang 1, 2, 3, ,

  • 1 Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
  • 2 Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China
  • 3 Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
* Equal contribution

received: February 26, 2016 ; accepted: April 6, 2017 ; published: April 17, 2017 ;

https://doi.org/10.18632/aging.101224
How to Cite

Abstract

Aberrant activation of sonic hedgehog (SHH)/glioma-associated oncogene homolog 1 (GLI1) pathway plays an important role in the tumorigenicity of malignant glioma cells and resistance to temozolomide (TMZ). Here we investigated the aspirin’s antineoplastic molecular route by targeting SHH/GLI1 pathway and examined the feasibility of aspirin combined with TMZ therapy. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) revealed that the activity of the SHH/GLI1 pathway was strongly inhibited by aspirin. Aspirin acted as the glioma growth-inhibitory and pro-apoptosis roles by inhibiting the SHH/GLI1 pathway and reprogramming the epithelial to mesenchymal transition (EMT). The immunofluorescence assay showed aspirin could prevent the nuclear translocation of GLI1 to inhibit its transcriptional regulation. The stable lentiviral overexpression of GLI1 reversed the DNA double strand breaks (DSBs) caused by the GANT61 and TMZ. Furthermore, aspirin combined with TMZ enhanced chemosensitivity and GLI1-induced chemoprotection was partly blocked by aspirin in vitro and in vivo. Collectively, aspirin has a therapeutic potential for SHH/GLI1 targeted therapy against glioma cells. Acquired activation of GLI1 protects glioma cells against TMZ therapy. Impairment of DNA DSBs repair activity might be involved in the route of aspirin-induced chemosensitivity. Combined aspirin with TMZ may be a promising strategy against malignant glioma.

Abbreviations

TMZ: temozolomide; qRT-PCR: quantitative real-time polymerase chain reaction; DSBs: double strand breaks; EMT: epithelial to mesenchymal transition; MGMT: O6-methylguanine-DNA methyltransferase; ASA: aspirin (acetylsalicylic acid); CCK-8: cell counting kit-8; PBS: phosphate-buffered saline; GAPDH: glyceraldehyde 3-phosphatedehydrogenase; U87 OE: U87 stably overexpressing GLI1 cell line; U87 KD: U87 knowdown GLI1 cell line; GBM: glioblastoma.