VHL loss predicts response to Aurora kinase A inhibitor in renal cell carcinoma cells

Ding,Xiao‑Fei; Zhou,Jun; Chen,Guang; Wu,Ying‑Liang

doi:10.3892/mmr.2018.9038

VHL loss predicts response to Aurora kinase A inhibitor in renal cell carcinoma cells

Authors:
- Xiao‑Fei Ding
- Jun Zhou
- Guang Chen
- Ying‑Liang Wu
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Affiliations: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China, Laboratory for Biological Medicine, School of Medicine, Taizhou University, Taizhou, Zhejiang 318000, P.R. China, Institute of Tumor, Taizhou University, Taizhou, Zhejiang 318000, P.R. China
Published online on: May 17, 2018 https://doi.org/10.3892/mmr.2018.9038
Pages: 1206-1210

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Abstract

The majority of molecular targets of anticancer agents are limited to a subset of patients, and therefore identification of more specific biomarkers that can be used to improve clinical outcomes is of increasing interest. The present study showed that von Hippel‑Lindau tumor suppressor (VHL) tumor‑suppressor activity may influence the therapeutic response to Aurora kinase A (AURKA) inhibitors in human renal cell carcinoma (RCC). VHL protein (pVHL) expression was evaluated by immunoblotting in the human RCC cell lines CAKI, ACHN, 786‑O, 769‑P and A498. The anti‑tumor activities of alisertib, an AURKA‑specific chemical inhibitor, were detected by Cell Counting Kit‑8 assay in vitro and mouse xenograft model in vivo. Additionally, the VHL‑mediated anti‑tumor activity was assessed in 769‑P and CAKI cells via the loss or gain of VHL. The results revealed that VHL‑deficient 786‑O, 769‑P and A498 cells were sensitive to alisertib. By contrast, alisertib‑resistant CAKI and ACHN cells expressed the wild type VHL gene. In addition, rescue or knockdown of VHL was observed to increase or decrease alisertib anti‑proliferation activity, respectively, in RCC cells. The inverse correlation between the VHL gene expression profile and alisertib sensitivity was further confirmed in human cancer xenografts models. Taken together, these results suggested that VHL loss could potentially serve as a biomarker for predicting the efficacy of AURKA inhibitors.

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1	Kidney cancer update the year in review in kidney cancer. Clin Adv Hematol Oncol. 13:327–329. 2015.PubMed/NCBI
2	Massari F, Di Nunno V, Ciccarese C, Graham J, Porta C, Comito F, Cubelli M, Iacovelli R and Heng DYC: Adjuvant therapy in renal cell carcinoma. Cancer Treat Rev. 60:152–157. 2017. View Article : Google Scholar : PubMed/NCBI
3	Posadas EM, Limvorasak S and Figlin RA: Targeted therapies for renal cell carcinoma. Nat Rev Nephrol. 13:496–511. 2017. View Article : Google Scholar : PubMed/NCBI
4	Cha TL, Chuang MJ, Wu ST, Sun GH, Chang SY, Yu DS, Huang SM, Huan SK, Cheng TC, Chen TT, et al: Dual degradation of aurora A and B kinases by the histone deacetylase inhibitor LBH589 induces G2-M arrest and apoptosis of renal cancer cells. Clin Cancer Res. 15:840–850. 2009. View Article : Google Scholar : PubMed/NCBI
5	Kurahashi T, Miyake H, Hara I and Fujisawa M: Significance of Aurora-A expression in renal cell carcinoma. Urol Oncol. 25:128–133. 2007. View Article : Google Scholar : PubMed/NCBI
6	Li Y, Zhou W, Wei L, Jin J, Tang K, Li C, Teh BT and Chen X: The effect of Aurora kinases on cell proliferation, cell cycle regulation and metastasis in renal cell carcinoma. Int J Oncol. 41:2139–2149. 2012. View Article : Google Scholar : PubMed/NCBI
7	Karthigeyan D, Prasad SB, Shandilya J, Agrawal S and Kundu TK: Biology of Aurora A kinase: Implications in cancer manifestation and therapy. Med Res Rev. 31:757–793. 2011.PubMed/NCBI
8	Borisa AC and Bhatt HG: A comprehensive review on Aurora kinase: Small molecule inhibitors and clinical trial studies. Eur J Med Chem. 140:1–19. 2017. View Article : Google Scholar : PubMed/NCBI
9	Lim SK and Gopalan G: Aurora-A kinase interacting protein 1 (AURKAIP1) promotes Aurora-A degradation through an alternative ubiquitin-independent pathway. Biochem J. 403:119–127. 2007. View Article : Google Scholar : PubMed/NCBI
10	Eckerdt F, Pascreau G, Phistry M, Lewellyn AL, DePaoli-Roach AA and Maller JL: Phosphorylation of TPX2 by Plx1 enhances activation of Aurora A. Cell Cycle. 8:2413–2419. 2009. View Article : Google Scholar : PubMed/NCBI
11	Huang Y, Li T, Ems-McClung SC, Walczak CE, Prigent C, Zhu X, Zhang X and Zheng Y: Aurora A activation in mitosis promoted by BuGZ. J Cell Biol. 217:107–116. 2018. View Article : Google Scholar : PubMed/NCBI
12	Korobeynikov V, Deneka AY and Golemis EA: Mechanisms for nonmitotic activation of Aurora-A at cilia. Biochem Soc Trans. 45:37–49. 2017. View Article : Google Scholar : PubMed/NCBI
13	Compérat E, Bièche I, Dargère D, Laurendeau I, Vieillefond A, Benoit G, Vidaud M, Camparo P, Capron F, Verret C, et al: Gene expression study of Aurora-A reveals implication during bladder carcinogenesis and increasing values in invasive urothelial cancer. Urology. 72:873–877. 2008. View Article : Google Scholar : PubMed/NCBI
14	Goktas S, Yildirim M, Suren D, Alikanoglu AS, Dilli UD, Bulbuller N, Sezer C and Yildiz M: Prognostic role of Aurora-A expression in metastatic colorectal cancer patients. J BUON. 19:686–691. 2014.PubMed/NCBI
15	Twu NF, Yuan CC, Yen MS, Lai CR, Chao KC, Wang PH, Wu HH and Chen YJ: Expression of Aurora kinase A and B in normal and malignant cervical tissue: High Aurora A kinase expression in squamous cervical cancer. Eur J Obstet Gynecol Reprod Biol. 142:57–63. 2009. View Article : Google Scholar : PubMed/NCBI
16	Xu J, Li H, Wang B, Xu Y, Yang J, Zhang X, Harten SK, Shukla D, Maxwell PH, Pei D and Esteban MA: VHL inactivation induces HEF1 and Aurora kinase A. J Am Soc Nephrol. 21:2041–2046. 2010. View Article : Google Scholar : PubMed/NCBI
17	Hasanov E, Chen G, Chowdhury P, Weldon J, Ding Z, Jonasch E, Sen S, Walker CL and Dere R: Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL. Oncogene. 36:3450–3463. 2017. View Article : Google Scholar : PubMed/NCBI
18	Gossage L, Eisen T and Maher ER: VHL, the story of a tumour suppressor gene. Nat Rev Cancer. 15:55–64. 2015. View Article : Google Scholar : PubMed/NCBI
19	Kim BJ, Kim JH, Kim HS and Zang DY: Prognostic and predictive value of VHL gene alteration in renal cell carcinoma: A meta-analysis and review. Oncotarget. 8:13979–13985. 2017.PubMed/NCBI
20	Ferchichi I, Kourda N, Sassi S, Romdhane KB, Balatgi S, Cremet JY, Prigent C and Elgaaied AB: Aurora A overexpression and pVHL reduced expression are correlated with a bad kidney cancer prognosis. Dis Markers. 33:333–340. 2012. View Article : Google Scholar : PubMed/NCBI