Abstract
BackgroundAdrenocortical 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.MethodsWe 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.ResultsKnocking 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.ConclusionsThese preclinical studies suggest that targeting p53 through PLK-1 is an attractive chemotherapy strategy warranting further investigation in adrenocortical cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s40169-015-0080-3) contains supplementary material, which is available to authorized users.
Highlights
Adrenocortical carcinoma (ACC) is an aggressive cancer with a 5 year survival rate of 20–30 %
In the present analysis of gene expression profiles of ACC tumor samples, we found overexpression of polo-like kinase 1 (PLK-1), which is known to negatively regulate p53 activity, in 29 % of the tumors in our cohort and in 67 % of the tumors from the cohort published by Giordano, et al [23]
Inhibition of Polo‐like kinase 1 (PLK‐1) reduced the viability of ACC cell lines Examination of our gene expression data [22] combined with that of Giordano, et al [23]. revealed that PLK1 was over-expressed in 37 % of tumors with a mean log2 foldchange relative to normal adrenal of 7.88
Summary
Adrenocortical carcinoma (ACC) is an aggressive cancer with a 5 year survival rate of 20–30 %. In the original phase II trial, etoposide, doxorubicin, and cisplatin in combination with mitotane (EDPM), was reported to produce clinical response rates up to 49 % of patients in advanced ACC patients [14], the results were not substantiated in the phase III trial comparing this regimen to streptozocin and mitotane. In this trial, the response rate to EDP-M was 23.2 % and the median progression-free survival interval was 5 months [15]. There is no approved second-line regimen for those whose disease progress on these agents
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