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HDM2 regulation by AURKA promotes cell survival in gastric cancer.

ABSTRACT: Suppression of P53 (tumor protein 53) transcriptional function mediates poor therapeutic response in patients with cancer. Aurora kinase A (AURKA) and human double minute 2 (HDM2) are negative regulators of P53. Herein, we examined the role of AURKA in regulating HDM2 and its subsequent effects on P53 apoptotic function in gastric cancer.Primary tumors and in vitro gastric cancer cell models with overexpression or knockdown of AURKA were used. The role of AURKA in regulating HDM2 and cell survival coupled with P53 expression and activity were investigated.Overexpression of AURKA enhanced the HDM2 protein level; conversely, knockdown of endogenous AURKA decreased expression of HDM2 in AGS and SNU-1 cells. Dual co-immunoprecipitation assay data indicated that AURKA was associated with HDM2 in a protein complex. The in vitro kinase assay using recombinant AURKA and HDM2 proteins followed by co-immunoprecipitation revealed that AURKA directly interacts and phosphorylates HDM2 protein in vitro. The activation of HDM2 by AURKA led to induction of P53 ubiquitination and attenuation of cisplatin-induced activation of P53 in gastric cancer cells. Inhibition of AURKA using an investigational small-molecule specific inhibitor, alisertib, decreased the HDM2 protein level and induced P53 transcriptional activity. These effects markedly decreased cell survival in vitro and xenograft tumor growth in vivo. Notably, analysis of immunohistochemistry on tissue microarrays revealed significant overexpression of AURKA and HDM2 in human gastric cancer samples (P < 0.05).Collectively, our novel findings indicate that AURKA promotes tumor growth and cell survival through regulation of HDM2-induced ubiquitination and inhibition of P53. Clin Cancer Res; 20(1); 76-86. ©2013 AACR.

SUBMITTER: Sehdev V

PROVIDER: S-EPMC3947328 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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HDM2 regulation by AURKA promotes cell survival in gastric cancer.

Sehdev Vikas V Katsha Ahmed A Arras Janet J Peng Dunfa D Soutto Mohammed M Ecsedy Jeffrey J Zaika Alexander A Belkhiri Abbes A El-Rifai Wael W

Clinical cancer research : an official journal of the American Association for Cancer Research 20131115 1

<h4>Purpose</h4>Suppression of P53 (tumor protein 53) transcriptional function mediates poor therapeutic response in patients with cancer. Aurora kinase A (AURKA) and human double minute 2 (HDM2) are negative regulators of P53. Herein, we examined the role of AURKA in regulating HDM2 and its subsequent effects on P53 apoptotic function in gastric cancer.<h4>Experimental design</h4>Primary tumors and in vitro gastric cancer cell models with overexpression or knockdown of AURKA were used. The role ...[more]

PMID: 24240108

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Project description:BackgroundThe primary cilia (PC) is a microtubule-based and nonmotile organelle which protrudes from the surface of almost all mammalian cells. At present, PC has been found to be a deficiency or loss in multiple cancers. Restoring PC could be a novel targeting therapy strategy. Our research showed that PC was reduced in human bladder cancer (BLCA) cells, and PC deficiency promotes cell proliferation. However, the concrete mechanisms remain unknown. SCL/TAL1 interrupting locus (STIL), a PC-related protein, was screened in our previous study and could influence the cell cycle by regulating PC in tumor cells. In this study, we aimed to elucidate the function of STIL for PC to explore the underlying mechanism of PC in BLCA.MethodsPublic database analysis, western blot, and enzyme-linked immunosorbent assay (ELISA) were used to screen genes and explore gene expression alteration. Immunofluorescence and western blot were utilized to investigate PC. Wound healing assay, clone formation assay, and CCK-8 assay were used to explore cell migration, growth, and proliferation. The co-immunoprecipitation and western blot were employed to reveal the interaction of STIL and AURKA.ResultsWe found that high STIL expression is correlated with poor outcomes of BLCA patients. Further analysis revealed that STIL overexpression could inhibit PC formation, activate SHH signaling pathways, and promote cell proliferation. In contrast, STIL-knockdown could promote PC formation, inactivate SHH signaling, and inhibit cell proliferation. Furthermore, we found that the regulatory functions of STIL for PC depend on AURKA. STIL could influence proteasome activity and maintain AURKA stabilization. AURKA-knockdown could reverse PC deficiency caused by STIL overexpression for PC in BLCA cells. We observed that co-knockdown in STIL and AURKA significantly enhanced PC assembly.ConclusionIn summary, our result provides a potential therapy target for BLCA based on the restoration of PC.

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HDM2 regulation by AURKA promotes cell survival in gastric cancer.

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HDM2 regulation by AURKA promotes cell survival in gastric cancer.

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