1. Academic Validation
  2. MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo

MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo

  • Mol Cancer Res. 2010 Mar;8(3):373-84. doi: 10.1158/1541-7786.MCR-09-0300.
Jessica J Huck 1 Mengkun Zhang Alice McDonald Doug Bowman Kara M Hoar Bradley Stringer Jeffery Ecsedy Mark G Manfredi Marc L Hyer
Affiliations

Affiliation

  • 1 Millennium Pharmaceuticals, Cambridge, MA 02139, USA.
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.

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