title: MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo.
abstract: Aurora A kinase is a serine/threonine protein kinase responsible for regulating several mitotic processes including centrosome separation, spindle assembly, and chromosome segregation. Small molecule inhibitors of Aurora A kinase are being pursued as novel anticancer agents, some of which have entered clinical trials. Despite the progress in developing these agents, terminal outcomes associated with Aurora A inhibition are not fully understood. Although evidence exists that Aurora A inhibition leads to apoptosis, other therapeutically relevant cell fates have not been reported. Here, we used the small molecule inhibitor MLN8054 to show that inhibition of Aurora A induces tumor cell senescence both in vitro and in vivo. Treatment of human tumor cells grown in culture with MLN8054 showed a number of morphologic and biochemical changes associated with senescence. These include increased staining of senescence-associated beta-galactosidase, increased nuclear and cell body size, vacuolated cellular morphology, upregulation/stabilization of p53, p21, and hypophosphorylated pRb. To determine if Aurora A inhibition induces senescence in vivo, HCT-116 xenograft-bearing animals were dosed orally with MLN8054 for 3 weeks. In the MLN8054-treated animals, increased senescence-associated beta-galactosidase activity was detected in tissue sections starting on day 15. In addition, DNA and tubulin staining of tumor tissue showed a significant increase in nuclear and cell body area, consistent with a senescent phenotype. Taken together, this data shows that senescence is a terminal outcome of Aurora A inhibition and supports the evaluation of senescence biomarkers in clinic samples.
authors.affiliation: Millennium Pharmaceuticals, Cambridge, MA 02139, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Huck
authors.forename: Mengkun
authors.initials: M
authors.lastname: Zhang
authors.forename: Alice
authors.initials: A
authors.lastname: McDonald
authors.forename: Doug
authors.initials: D
authors.lastname: Bowman
authors.forename: Kara M
authors.initials: KM
authors.lastname: Hoar
authors.forename: Bradley
authors.initials: B
authors.lastname: Stringer
authors.forename: Jeffery
authors.initials: J
authors.lastname: Ecsedy
authors.forename: Mark G
authors.initials: MG
authors.lastname: Manfredi
authors.forename: Marc L
authors.initials: ML
authors.lastname: Hyer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D045744:Cell Line, Tumor; D048429:Cell Size / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism; D001616:beta-Galactosidase / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001552:Benzazepines; D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; C518940:MLN8054; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D001616:beta-Galactosidase