Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma

Abstract

The Aurora kinases A and B control tumorigenesis by inhibiting apoptosis and promoting proliferation and metastasis, however, it remains unknown whether Aurora A and B overexpressed concomitantly and its clinical significance in hepatocellular carcinoma (HCC). Here, we obsearved Aurora A and B tended to overexpress parallelly on protein level (r = 0.8679, P < 0.0001) and their co-overexpression (Aurora AHBH), associated with the worst prognosis, was an independent predictor for the survival. Importantly, with the lower IC50 and stronger anti-tumor effect than selective inhibitors, SNS-314, the pan-inhibitor of Aurora kinases, which induced YAP (Yes-associated protein) reduction and resulted in P21 accumulation, significantly promoted the polyploidy (> 4N) formation and apoptosis in HCC. High YAP expression (YAPH) was associated with Aurora AHBH, and appeared to be an independent predictor for survival, but P21 not. Moreover, silencing YAP also induced P21 accumulation, and knockdown P21, which enhanced YAP accumulation and weakened the SNS-314-induced YAP reduction, impaired SNS-314-induced apoptosis. Therefore, P21 enhanced the apoptotic effect of SNS-314 in HCC. Taken together, our findings indicated Aurora kinases/YAP/P21 was an oncogenic signaling axis in HCC, and revealed targeting Aurora AHBH induced apoptosis by YAP suppression. Our results also provided a solid evidence for SNS-314 as a potential targeted therapy, and a proof-of-concept evidence for a possible combined therapy of SNS-314 plus Hippo pathway inhibitors on HCC.

Activation of Aurora A kinase increases YAP stability via blockage of autophagy

“…In addition, Aurora A can, through activating the mTOR pathway in breast cancer, block the autophagy, which has been proved to be essential for maintaining and promoting cellular homeostasis 36–38 . As a result, Aurora A is considered as a promising molecular target for cancer therapy 39–42 .…”

Integrated multi‑omics data analysis identifying novel drug sensitivity‑associated molecular targets of hepatocellular carcinoma cells

“…In addition, all three proteins are overexpressed in numerous types of cancer ( 41 ). In cancer cells, including HCC, Aurora kinases inhibit apoptosis and promote cellular proliferation and metastasis ( 42 ). AURKA is directly associated with the EGFR/PI3K/Akt/mTOR pathway, since active EGFR signaling is able to upregulate expression of AURKA through the FR/PI3K/Akt/mTOR signaling axis ( 43 ).…”

Deguelin, an Aurora B Kinase Inhibitor, Exhibits Potent Anti-Tumor Effect in Human Esophageal Squamous Cell Carcinoma

“…Aurora B was first demonstrated to be overexpressed in colon cancer in 1998 ( Bischoff et al, 1998 ). Cumulative evidence indicated that the amplification/overexpression and/or hyperactivation of Aurora B kinase is a frequent finding in a panel of human malignancies, such as breast ( Larsen et al, 2015 , Zhang et al, 2015 ), liver ( Liu et al, 2017 ), lung ( Al-Khafaji et al, 2017 , Helfrich et al, 2016 ), prostate ( Schecher et al, 2017 , Zekri et al, 2017 ) cancer and leukemia ( Floc'h et al, 2017 , Song et al, 2017 ). The evidence linking Aurora B overexpression and malignancy has generated significant interest in the development of small-molecule inhibitors against this protein.…”