title: Annexin A5 promotes invasion and chemoresistance to temozolomide in glioblastoma multiforme cells.
abstract: Glioblastoma multiforme (GBM) is the prevalent and most fatal brain tumor in adults. Invasion and a high rate of recurrence largely contribute to the poor prognosis of GBM. The current standard therapy for GBM includes surgery with maximum feasible resection, radiotherapy, and treatment with chemotherapeutic agent temozolomide. Annexin A5 reportedly promotes progression and chemoresistance in a variety of cancers. In the present study, we explored the effects of annexin A5 on GBM cell invasion and chemoresistance to temozolomide. Stable overexpression and knockdown of annexin A5 were performed in both U-87 MG and U-118 MG human GBM cell lines. Overexpression of annexin A5 in both cell lines significantly increased cell invasion, matrix metalloproteinase-2 (MMP-2) expression/activity, Akt phosphorylation at serine 473, and the half maximal inhibitory concentration (IC50) values of temozolomide and markedly decreased temozolomide-induced apoptosis, all of which were abolished by selective PI3K inhibitor BKM120. On the other hand, knockdown of annexin A5 markedly decreased cell invasion, MMP-2 expression/activity, Akt phosphorylation at serine 473, and the IC50 values of temozolomide and significantly increased temozolomide-induced apoptosis. In conclusion, our study provides the first evidence that annexin A5 promotes GBM cell invasion, MMP-2 expression/activity, and chemoresistance to temozolomide through a PI3K-dependent mechanism. It adds new insights not only into the biological function of annexin A5 but also into the molecular mechanisms underlying GBM progression and chemoresistance.
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital, Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
authors.forename: Liang
authors.initials: L
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Xiong
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Shen
authors.forename: Zujue
authors.initials: Z
authors.lastname: Cheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ziyun
authors.initials: Z
authors.lastname: Gao
authors.forename: Xingen
authors.initials: X
authors.lastname: Zhu
mesh_terms: D017304:Annexin A5 / Q000235:genetics* / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D000077204:Temozolomide; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D017304:Annexin A5; D018906:Antineoplastic Agents, Alkylating; D015820:Cadherins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D003606:Dacarbazine; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; D000077204:Temozolomide