Relation of AURKB over-expression to low survival rate in BCRA and reversine-modulated aurora B kinase in breast cancer cell lines

Abstract

Background New therapeutic drug for breast cancer (BRCA), especially triple negative BRCA (TNBC), is urgently needed. Even though 2-(4-morpholinoanilino)-6-cyclohexylaminopurine (reversine) is an aurora kinase inhibitor, it also inhibits some cancer cells and human BRCA cells. However, the potential roles of reversine as a novel therapeutic agent for the treatment of BRCA remains unknown and must be further investigation. Thus, the relationship of reversine to aurora kinase in BCRA has not been reported. The relationship between AURKB and survival rate in BRCA has never been reported. Herein, we tested the roles of reversine on different BRCA cell line subtypes. We also investigated the relationship between AURKB and survival rate in BRCA as well as reversine to Aurora kinase expression in BCRA cell lines, including TNBC subtype, 4T1, MDA-MB-231, and luminal subtype MCF-7. Methods Cell viability and apoptosis were detected using Cell Counting Kit-8 and flow cytometry analysis, respectively. Apoptotic and tumor-related proteins were tested using Western blot analysis. Important microRNAs that regulate BRCA were analyzed using RT-PCR. UALCAN public databases were used to analyze the targeted gene profiles, and the PROGgeneV2 database was used to study the prognostic implications of genes. Results Reversine inhibits cell proliferation and induces cell apoptosis by modulating caspase-3 and bax/bcl-2 among the three cell lines. Data from the UALCAN public database show that BRCA tissues expressed high gene levels of AURKB, TIMP1, MMP9 , and TGFB1 compared with the normal tissue. Among the over-expressed genes in BRCA, AURKB ranks 9th in TNBC, 49th in luminal subtype, and 48th in HER2 subtype. High AURKB level in BRCA is highly related to the low survival rate in patients displayed in 18 databases searched via PROGgeneV2. The protein levels of aurora B kinase (Aurora B), which is encoded by AURKB gene, are highly suppressed by reversine in the three cell lines. The tumor-related proteins TGF-β1, TIMP1, and MMP9 are partially suppressed by reversine but with different sensitivity in the three cell lines. The reversine-affected microRNAs, such as miR129-5p, miR-199a-3p, and miR-3960, in MDA-MB-231 cell line might be the research targets in TNBC regulation. Conclusions In BRCA, the level of AURKB are over-expressed and is related to low survival rate. Reversine contributes to anti-growth effect in BRCA cell lines, especially for TNBC, by modulating the aurora B. However, the invasiveness, metastasis, and anti-tumor effects of reversine in vivo and in vitro must be further investigated. Electronic supplementary material The online version of this article (10.1186/s12935-019-0885-z) contains supplementary material, which is available ...

Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer

“…Likewise, AURKB was found to be induced in the squamous carcinoma subtype of NSCLC and the expression level of AURKB also served as a marker for resistance to paclitaxel, a drug commonly used in the treatment of NSCLC [ 31 ]. Similar to NSCLC, metastatic colorectal cancer patients lived significantly shorter when they had high levels of AURKB expression in their tumor tissues [ 32 ] and the publicly available databases further showed that increased AURKB expression also correlated significantly with reduced survival in breast cancer patients [ 33 ]. AURKB expression has been identified as a prognostic biomarker in glioblastoma [ 34 ], gastric cancer [ 35 ] and oral cancer [ 36 , 37 , 38 ].…”

“…Additionally, PHA680632 [ 139 ], reversine [ 33 , 140 ], CCT129202 [ 141 ], CCT137690 [ 142 , 143 ], SNS-314 [ 144 ], quercetin [ 145 , 146 ] are pan-aurora kinase inhibitors that have been tested in pre-clinical studies. Furthermore, VX-680 [ 147 , 148 , 149 ] and BI 811283 [ 108 , 109 ] are pan-AURK inhibitors that have been studied in clinical trials.…”

Multiple functions of reversine on the biological characteristics of sheep fibroblasts

“…Aurora kinase family comprises serine/threonine kinases that play critical roles in cell-cycle progression, chromosome alignment and cytokinesis during mitosis, and consists of three members: Aurora A, B and C. Aberrant expression of aurora kinases has been reported in human solid and hematological cancers 10 – 12 . Aurora B, the catalytic subunit of chromosomal passenger complex (CPC), is involved in multiple mitotic functions, and therefore dysfunction of its kinase activity will cause segregation barrier of chromosomes, central spindle assembly impairment, and phosphorylation of histone H3 13 , 14 .…”

CASP9 As a Prognostic Biomarker and Promising Drug Target Plays a Pivotal Role in Inflammatory Breast Cancer

“…AURKB plays a key role during mitosis [19].The role of the AURKB expression in cancer prognosis is controversial. AURKB was found to be correlated with the cell proliferation and AURKB expression is an independent prognostic index of breast cancer, especially for triple negative breast cancer (TNBC) [20,21]. While AURKB expression was reported to be not associated with the survival of breast cancer patients [22].…”