Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma
Fuchen Liu1,2, Guangyong Wang3, Xiaoqiang Wang4
1The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
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.
Insights
Aurora kinases A and B are co-overexpressed in hepatocellular carcinoma (HCC), predicting poor survival. Targeting these kinases with SNS-314 induces apoptosis via YAP suppression, offering a potential therapy for HCC.
Area of Science:
- Oncology
- Molecular Biology
- Hepatocellular Carcinoma Research
Background:
- Aurora kinases A and B regulate tumorigenesis by affecting apoptosis, proliferation, and metastasis.
- The concurrent overexpression and clinical significance of Aurora A and B in hepatocellular carcinoma (HCC) were previously unknown.
Purpose of the Study:
- To investigate the co-overexpression of Aurora kinases A and B in HCC and its clinical significance.
- To evaluate the anti-tumor effect of the Aurora kinase pan-inhibitor SNS-314 in HCC.
- To elucidate the underlying mechanisms of SNS-314, including its effects on YAP and P21, and their roles in apoptosis.
Main Methods:
- Protein expression analysis of Aurora A and B in HCC tissues.
- Correlation analysis between Aurora A and B expression and patient survival.
- In vitro studies using SNS-314 to assess its efficacy, IC50, and effects on YAP, P21, polyploidy, and apoptosis in HCC cells.
- Gene silencing experiments for YAP and P21 to determine their roles in SNS-314's anti-tumor activity.
Main Results:
- Aurora A and B were found to be parallelly overexpressed in HCC, with co-overexpression (Aurora AHBH) serving as an independent predictor of poor survival.
- SNS-314 demonstrated a lower IC50 and stronger anti-tumor effect compared to selective inhibitors, inducing polyploidy and apoptosis.
- SNS-314 treatment led to YAP reduction and P21 accumulation; high YAP expression correlated with Aurora AHBH and predicted survival.
- Silencing YAP induced P21 accumulation, while P21 knockdown impaired SNS-314-induced apoptosis and enhanced YAP accumulation, indicating P21 enhances SNS-314's apoptotic effect.
Conclusions:
- The Aurora kinases/YAP/P21 axis is oncogenic in HCC.
- Targeting co-overexpressed Aurora kinases (Aurora AHBH) induces apoptosis through YAP suppression.
- SNS-314 shows promise as a targeted therapy for HCC, with potential for combination therapy with Hippo pathway inhibitors.
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