Inhibition of FoxO1 nuclear exclusion prevents metastasis of glioblastoma.
Glioblastoma is the most aggressive malignant primary brain tumor in humans, with extremely poor patient survival. Although previous studies have demonstrated that expression of matrix metalloproteinase-9 (MMP9) in glioblastoma promotes cancer metastasis, the upstream molecular signaling cascades that control activation of MMP9 remain largely unknown. Here, we used a human glioblastoma line, A-172, to examine molecular signaling to activate MMP9. We found that epidermal growth factor (EGF)-induced activation of epidermal growth factor receptor (EGFR) in A-172 cells activated MMP9, resulting in an increase in cancer invasiveness. A specific inhibitor for EGFR efficiently blocked EGF-induced activation of MMP9 and then cancer invasiveness. Moreover, an inhibitor for phosphatidylinositol 3-kinase (PI-3 K)/protein kinase B (Akt) significantly inhibited the EGF-induced activation of MMP9. Furthermore, nuclear exclusion of a major Akt downstream target, Forkhead box protein O1 (FoxO1), was induced by Akt activation, which could be inhibited by either an EGFR inhibitor or by PI-3 K/Akt inhibitor. An expression of a constitutive nuclear form of FoxO1 significantly inhibited MMP9 activation induced by EGF. Taken together, these findings suggest that EGF/EGFR signaling activates downstream PI-3 K/Akt to induce FoxO1 nuclear exclusion, which activates MMP9 to promote glioblastoma invasiveness. Thus, FoxO1 appears to be a novel therapeutic target for inhibiting metastasis of glioblastoma.
Neurosurgery Department, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
Jin
J
Chen
Qin
Q
Huang
Feng
F
Wang
D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D066246:ErbB Receptors / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
D004791:Enzyme Inhibitors; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9