The negative interplay between Aurora A/B and BRCA1/2 controls cancer cell growth and tumorigenesis via distinct regulation of cell cycle progression, cytokinesis, and tetraploidy

Molecular Cancer

Research

Na Zhang¹  Ziliang Wang¹  Jiao Meng¹  Mingming Liu¹  Yan Wang¹  Zihao Qi¹  Gong Yang²  Sheng Yin³  Rongyu Zang³  Yang Liu³  Zhen Zhang⁴ 

[1] Cancer Institute, Fudan University Shanghai Cancer Center, 200032, Shanghai, China;Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China;Cancer Institute, Fudan University Shanghai Cancer Center, 200032, Shanghai, China;Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China;Center Laboratory, The Fifth People’s Hospital of Shanghai, Fudan University, 128 Ruili Road, 2000240, Shanghai, China;Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, 200032, Shanghai, China;Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China;Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 200032, Shanghai, China;Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China;

关键词: Aurora A/B;    BRCA1/2;    Cell cycle;    Cytokinesis;    Tetraploidy;    Tumorigenesis;   

DOI  :  10.1186/1476-4598-13-94

 received in 2013-09-10, accepted in 2014-04-16,  发布年份 2014

来源: Springer

【 摘 要 】

It is well known that the activation of Aurora A/B (Aur A/B) or inactivation of BRCA1/2 induces tumor formation. Others and we have reported that the mutual suppression between Aur A/B and BRCA1/2 may manipulate cancer cell growth and tumorigenesis, however, the interactive regulation and mechanism between these molecules are still elusive. In this study, by consecutive silencing of Aur A/B or/and BRCA1/2 with specific shRNAs, we showed that, in BRCA2-deficient pancreatic cancer cell line Capan-1 and in ovarian cancer cell line OVCA433, Aur A/B and BRCA1/2 inversely regulated the expression of each other likely through proteasome-mediated proteolysis but not through gene transcription. Aur A/B and BRCA1/2 conversely regulated cell cycle progression mainly through control of p53 and cyclin A. Moreover, the disruption of Aur A/B blocked abnormal cytokinesis and decreased cell multinuclearity and chromosome tetraploidy, whereas the deprivation of BRCA1/2 promoted the abnormal cytokinesis and enhanced the cell multinuclearity and tetraploidy. Furthermore, we showed by animal assays that the depletion of Aur A/B inhibited tumor growth of both cell lines, while the knockdown of BRCA1/2 promoted the tumor growth. However, the concurrent silencing of Aur A/B and BRCA1/2 diminished the effects of these molecules on the regulation of cell cycle, cytokinesis, and tetraploidy, leading to the burdened tumor sizes similar to those induced by scrambled shRNA-treated control cells. In summary, our study revealed that the negative interplay between Aur A/B and BRCA1/2 inversely controls the cell proliferation, cell cycle progression, cell multinuclearity, and tetraploidization to modulate tumorigenesis.

【 授权许可】

Unknown   
© Wang et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.