title: Targeting polo-like kinase 1, a regulator of p53, in the treatment of adrenocortical carcinoma.
abstract: BACKGROUND
  Adrenocortical carcinoma (ACC) is an aggressive cancer with a 5 year survival rate of 20-30 %. Various factors have been implicated in the pathogenesis of ACC including dysregulation of the G2/M transition and aberrant activity of p53 and MDM2. Polo-like kinase 1 (PLK-1) negatively modulates p53 functioning, promotes MDM2 activity through its phosphorylation, and is involved in the G2/M transition. Gene expression profiling of 44 ACC samples showed that increased expression of PLK-1 in 29 % of ACC. Consequently, we examined PLK-1's role in the modulation of the p53 signaling pathway in adrenocortical cancer.
  
  
  METHODS
  We used siRNA knock down PLK-1 and pharmacological inhibition of PLK-1 and MDM2 ACC cell lines SW-13 and H295R. We examined viability, protein expression, p53 transactivation, and induction of apoptosis.
  
  
  RESULTS
  Knocking down expression of PLK-1 with siRNA or inhibition of PLK-1 by a small molecule inhibitor, BI-2536, resulted in a loss of viability of up to 70 % in the ACC cell lines H295R and SW-13. In xenograft models, BI-2536 demonstrated marked inhibition of growth of SW-13 with less inhibition of H295R. BI-2536 treatment resulted in a decrease in mutant p53 protein in SW-13 cells but had no effect on wild-type p53 protein levels in H295R cells. Additionally, inhibition of PLK-1 restored wild-type p53's transactivation and apoptotic functions in H295R cells, while these functions of mutant p53 were restored only to a smaller extent. Furthermore, inhibition of MDM2 with nutlin-3 reduced the viability of both the ACC cells and also reactivated wild-type p53's apoptotic function. Inhibition of PLK-1 sensitized the ACC cell lines to MDM2 inhibition and this dual inhibition resulted in an additive apoptotic response in H295R cells with wild-type p53.
  
  
  CONCLUSIONS
  These preclinical studies suggest that targeting p53 through PLK-1 is an attractive chemotherapy strategy warranting further investigation in adrenocortical cancer.
authors.affiliation: NantOmics, LLC, The Biodesign Institute, Arizona State University, PO Box 875001, Tempe, AZ, 85287-5001, USA. Kimberly.Bussey@asu.edu.|Translational Genomics Research Institute (TGen), Phoenix, AZ, USA. Kimberly.Bussey@asu.edu.
authors.forename: Kimberly J
authors.identifier: http://orcid.org/0000-0003-1001-8207
authors.initials: KJ
authors.lastname: Bussey
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, AZ, USA. aditi.a.bapat@gmail.com.
authors.forename: Aditi
authors.initials: A
authors.lastname: Bapat
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, AZ, USA. clairelinnehan@gmail.com.
authors.forename: Claire
authors.initials: C
authors.lastname: Linnehan
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, AZ, USA. Melissa.wando@gmail.com.
authors.forename: Melissa
authors.initials: M
authors.lastname: Wandoloski
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, AZ, USA. erica.dastrup@gmail.com.
authors.forename: Erica
authors.initials: E
authors.lastname: Dastrup
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, AZ, USA. Erik.G.Rogers@asu.edu.
authors.forename: Erik
authors.initials: E
authors.lastname: Rogers
authors.affiliation: Translational Drug Development (TD2), Scottsdale, AZ, USA. pgonzales@td2inc.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Gonzales
authors.affiliation: Translational Genomics Research Institute (TGen), Phoenix, AZ, USA. mdemeure@tgen.org.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Demeure
keywords: Adrenocortical carcinoma; PLK-1; Targeted therapy; p53