title: Aurora A is differentially expressed in gliomas, is associated with patient survival in glioblastoma and is a potential chemotherapeutic target in gliomas.
abstract: Aurora A is critical for mitosis and is overexpressed in several neoplasms. Its overexpression transforms cultured cells, and both its overexpression and knockdown cause genomic instability. In transgenic mice, Aurora A haploinsufficiency, not overexpression, leads to increased malignant tumor formation. Aurora A thus appears to have both tumor-promoting and tumor-suppressor functions. Here, we report that Aurora A protein, measured by quantitative protein gel blotting, is differentially expressed in major glioma types in lineage-specific patterns. Aurora A protein levels in WHO grade II oligodendrogliomas (n=16) and grade III anaplastic oligodendrogliomas (n=16) are generally low, similar to control epilepsy cerebral tissue (n=11). In contrast, pilocytic astrocytomas (n=6) and ependymomas (n=12) express high Aurora A levels. Among grade II to grade III astrocytomas (n=7, n=14, respectively) and grade IV glioblastomas (n=31), Aurora A protein increases with increasing tumor grade. We also found that Aurora A expression is induced by hypoxia in cultured glioblastoma cells and is overexpressed in hypoxic regions of glioblastoma tumors. Retrospective Kaplan-Meier analysis revealed that both lower Aurora A protein measured by quantitative protein gel blot (n=31) and Aurora A mRNA levels measured by real-time quantitative RT-PCR (n=58) are significantly associated with poorer patient survival in glioblastoma. Furthermore, we report that the selective Aurora A inhibitor MLN8237 is potently cytotoxic to glioblastoma cells, and that MLN8237 cytotoxicty is potentiated by ionizing radiation. MLN8237 also appeared to induce senescence and differentiation of glioblastoma cells. Thus, in addition to being significantly associated with survival in glioblastoma, Aurora A is a potential new drug target for the treatment of glioblastoma and possibly other glial neoplasms.
authors.affiliation: Department of Pathology and Laboratory Medicine, The Hermelin Brain Tumor Center, Henry Ford Hospital, and Department of Pathology, Wayne State University, Detroit, MI, USA. nllehman@yahoo.com
authors.forename: Norman L
authors.initials: NL
authors.lastname: Lehman
authors.forename: James P
authors.initials: JP
authors.lastname: O'Donnell
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Whiteley
authors.forename: Robert T
authors.initials: RT
authors.lastname: Stapp
authors.forename: Trang D
authors.initials: TD
authors.lastname: Lehman
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Roszka
authors.forename: Lonni R
authors.initials: LR
authors.lastname: Schultz
authors.forename: Caitlin J
authors.initials: CJ
authors.lastname: Williams
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Brown
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Ecsedy
authors.forename: Laila M
authors.initials: LM
authors.lastname: Poisson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines / Q000633:toxicity; D015415:Biomarkers / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D002648:Child; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D011839:Radiation, Ionizing; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D001381:Azepines; D015415:Biomarkers; C550258:MLN 8237; D011743:Pyrimidines; D012333:RNA, Messenger; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases