Role of aurora kinase B in regulating resistance to paclitaxel in breast cancer cells

Min Liu,Yinan Li,Cui Zhang,Qing Zhang

doi:10.1007/s13577-022-00675-8

Abstract

Aurora kinase B (AURKB) is a type of functional kinase with primary functions of participating in cell mitosis, which has been identified to be involved in the occurrence and development of malignant tumors strongly. However, it still remains a controversial with respect to the relationship between the phosphorylation level of AURKB and its function. In our initial research, there was no significant difference in the relative content of AURKB protein between drug-resistant breast cancer cells and wild-type cells; however, its phosphorylation level in drug-resistant cells was significantly higher than that in wild-type cells. Subsequent cell and animal experiments both confirmed the positive correlation between AURKB phosphorylation and drug resistance. Furthermore, PRKCE in the upstream was identified to regulate the phosphorylation of AURKB, which promoted the change of spatial localization of AURKB from nucleus to cytoplasm. Accordingly, phosphorylated AURKB reduced the negative regulation of downstream RAB27B transcription physically, and interacted with RAB27B in cytoplasm to maintain its protein stability. Eventually, it promoted exosome secretion of drug-resistant cells and drug efflux. Using shRNA to knockdown AURKB expression, using hesperadin to inhibit AURKB activity, mutating the AURKB phosphorylation site, or using siRNA as well as BIM to inhibit the activity of the upstream AURKB phosphorylation regulatory protein PRKCE, all of which directly or indirectly reduce AURKB phosphorylation, are effective in reversing PTX resistance in cells. Collectively, this study provides experimental evidence for PRKCE/AURKB/RAB27B axis in regulating the resistance to paclitaxel (PTX) in breast cancer cells, offering a potential intervention target for reversing drug resistance.

Highlights

Aurora kinases, which were first discovered in Drosophila melanogaster, are serine/threonine kinases that play important roles in cell cycle regulation [1]
High expression of Aurora kinase B (AURKB) in breast cancer tissues and cells According to the analysis of breast cancer data in TCGA using the online tool ACLBI, AURKB was abnormally highly expressed in breast cancer tissues (Fig. 1a)
The AURKB protein was relatively highly expressed in breast cancer tissues, as revealed by immuno-histochemical detection (Fig. 1c)

Summary

Introduction

Aurora kinases, which were first discovered in Drosophila melanogaster, are serine/threonine kinases that play important roles in cell cycle regulation [1]. This family is named Aurora since mutation of its members causes the Aurora kinase B (AURKB) is a functional kinase located in the centrosome of the nucleus. Recent studies speculated that its functions in mitosis include (1) chromosome condensation; (2) formation of bipolar spindles; (3) chromosome attachment in the mitotic spindle; (4) adjustment of the spindle checkpoint; and (5) completion of cytoplasmic division [7, 8].

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Results

Conclusion