Targeting polo-like kinase 1, a regulator of p53, in the treatment of adrenocortical carcinoma

被引:25
作者
Bussey, Kimberly J. [1 ,2 ]
Bapat, Aditi [2 ]
Linnehan, Claire [2 ]
Wandoloski, Melissa [2 ]
Dastrup, Erica [2 ]
Rogers, Erik [2 ]
Gonzales, Paul [3 ]
Demeure, Michael J. [2 ]
机构
[1] Arizona State Univ, NantOmics LLC, POB 875001, Tempe, AZ 85287 USA
[2] Translat Genom Res Inst TGen, Phoenix, AZ 85004 USA
[3] Translat Drug Dev, Scottsdale, AZ USA
来源
CLINICAL AND TRANSLATIONAL MEDICINE | 2016年 / 5卷
关键词
Adrenocortical carcinoma; PLK-1; p53; Targeted therapy;
D O I
10.1186/s40169-015-0080-3
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页数:14
相关论文
共 49 条
[21]   Clinical management of adrenocortical carcinoma [J].
Fassnacht, Martin ;
Allolio, Bruno .
BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM, 2009, 23 (02) :273-289
[22]   Phase I study of the Plk1 inhibitor BI 2536 administered intravenously on three consecutive days in advanced solid tumours [J].
Frost, A. ;
Mross, K. ;
Steinbild, S. ;
Hedbom, S. ;
Unger, C. ;
Kaiser, R. ;
Trommeshauser, D. ;
Munzert, G. .
CURRENT ONCOLOGY, 2012, 19 (01) :E28-E35
[23]   A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors [J].
Garland, Linda L. ;
Taylor, Charles ;
Pilkington, Deborah L. ;
Cohen, Jan L. ;
Von Hoff, Daniel D. .
CLINICAL CANCER RESEARCH, 2006, 12 (17) :5182-5189
[24]   Molecular Classification and Prognostication of Adrenocortical Tumors by Transcriptome Profiling [J].
Giordano, Thomas J. ;
Kuick, Rork ;
Else, Tobias ;
Gauger, Paul G. ;
Vinco, Michelle ;
Bauersfeld, Juliane ;
Sanders, Donita ;
Thomas, Dafydd G. ;
Doherty, Gerard ;
Hammer, Gary .
CLINICAL CANCER RESEARCH, 2009, 15 (02) :668-676
[25]   Beyond Li Fraumeni Syndrome: Clinical Characteristics of Families With p53 Germline Mutations [J].
Gonzalez, Kelly D. ;
Noltner, Katie A. ;
Buzin, Carolyn H. ;
Gu, Dongqing ;
Wen-Fong, Cindy Y. ;
Nguyen, Vu Q. ;
Han, Jennifer H. ;
Lowstuter, Katrina ;
Longmate, Jeffrey ;
Sommer, Steve S. ;
Weitzel, Jeffrey N. .
JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (08) :1250-1256
[26]   PTTG/securin activates expression of p53 and modulates its function [J].
Hamid, Tariq ;
Kakar, Sham S. .
MOLECULAR CANCER, 2004, 3 (1)
[27]   Functional Genomics Reveals Diverse Cellular Processes That Modulate Tumor Cell Response to Oxaliplatin [J].
Harradine, Kelly A. ;
Kassner, Michelle ;
Chow, Donald ;
Aziz, Meraj ;
Von Hoff, Daniel D. ;
Baker, Joffre B. ;
Yin, Hongwei ;
Pelham, Robert J. .
MOLECULAR CANCER RESEARCH, 2011, 9 (02) :173-182
[28]   TP53 Germline Mutations in Adult Patients with Adrenocortical Carcinoma [J].
Herrmann, Leonie J. M. ;
Heinze, Britta ;
Fassnacht, Martin ;
Willenberg, Holger S. ;
Quinkler, Marcus ;
Reisch, Nicole ;
Zink, Martina ;
Allolio, Bruno ;
Hahner, Stefanie .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2012, 97 (03) :E476-E485
[29]   INDUCTION AND DOWN-REGULATION OF PLK, A HUMAN SERINE/THREONINE KINASE EXPRESSED IN PROLIFERATING CELLS AND TUMORS [J].
HOLTRICH, U ;
WOLF, G ;
BRAUNINGER, A ;
KARN, T ;
BOHME, B ;
RUBSAMENWAIGMANN, H ;
STREBHARDT, K .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (05) :1736-1740
[30]   Exploration, normalization, and summaries of high density oligonucleotide array probe level data [J].
Irizarry, RA ;
Hobbs, B ;
Collin, F ;
Beazer-Barclay, YD ;
Antonellis, KJ ;
Scherf, U ;
Speed, TP .
BIOSTATISTICS, 2003, 4 (02) :249-264