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Combined inhibition of AURKA and HSF1 suppresses proliferation and promotes apoptosis in hepatocellular carcinoma by activating endoplasmic reticulum stress

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Abstract

Purpose

In this study we aimed to assess the anti-tumor effect of co-inhibition of Aurora kinase A (AURKA) and heat shock transcription factor 1 (HSF1) on hepatocellular carcinoma (HCC), as well as to explore the mechanism involved.

Methods

Expression of AURKA and HSF1 in primary HCC tissues and cell lines was detected by immunohistochemistry (IHC), qRT-PCR and Western blotting. AURKA was knocked down in HepG2 and BEL-7402 HCC cells using lentivirus-mediated RNA interference. Next, CCK-8, clone formation, transwell and flow cytometry assays were used to assess their viability, migration, invasion and apoptosis, respectively. The expression of proteins related to cell cycle progression, apoptosis and endoplasmic reticulum stress (ERS) was analyzed using Western blotting. In addition, in vivo tumor growth of HCC cells was assessed using a nude mouse xenograft model, and the resulting tumors were evaluated using HE staining and IHC.

Results

Both AURKA and HSF1 were highly expressed in HCC tissues and cells, while being negatively related to HCC prognosis. Knockdown of AURKA significantly inhibited the colony forming and migrating capacities of HCC cells. In addition, we found that treatment with an AURKA inhibitor (Danusertib) led to marked reductions in the proliferation and migration capacities of the HCC cells, and promoted their apoptosis. Notably, combined inhibition of AURKA and HSF1 induced HCC cell apoptosis, while increasing the expression of ERS-associated proteins, including p-eIF2α, ATF4 and CHOP. Finally, we found that co-inhibition of AURKA and HSF1 elicited an excellent in vivo antitumor effect in a HCC mouse model with a relatively low cytotoxicity.

Conclusions

Combined inhibition of AURKA and HSF1 shows an excellent anti-tumor effect on HCC cells in vitro and in vivo, which may be mediated by ERS. These findings suggest that both AURKA and HSF1 may serve as targets for HCC treatment.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

AURKA:

aurora kinase A

HSF1:

heat shock transcription factor 1

HCC:

hepatocellular carcinoma

IHC:

immunohistochemistry

ERS:

endoplasmic reticulum stress

FBS:

fetal bovine serum

siRNA:

small-interfering RNA

CCK-8:

Cell Counting Kit-8

HE:

hematoxylin-eosin

UPR:

unfolded protein response

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Funding

This work was supported by grants from the Nanjing Municipal Science and Technology Committee of Jiangsu Province, China (grant number: 201803050) and the Jiangsu Post-doctoral Research Funding Program, China (grant number: 2020Z305).

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Authors and Affiliations

  1. The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, Jiangsu, 210009, China

    Zetian Shen, Li Yin & Xia He

  2. Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, 210002, Nanjing, Jiangsu, China

    Zetian Shen, Han Zhou, Xiaoqin Ji, Changchen Jiang & Xixu Zhu

Authors
  1. Zetian Shen
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  2. Li Yin
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  3. Han Zhou
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  5. Changchen Jiang
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  6. Xixu Zhu
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  7. Xia He
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Contributions

ZS and XH conceived and designed this study; LY, HZ, XJ and CJ performed the experiments and data analyses; ZS and XZ drafted the manuscript; XH provided critical comments, suggestions and revised the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Xia He.

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Conflict of interest

The authors declare that they have no competing interests.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Jinling Hospital, and written informed consent was obtained from all participating patients. The animal experiments were approved by the Ethics Committee of Jinling Hospital (approval no: 2020JLHGKJDWLS-140).

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Shen, Z., Yin, L., Zhou, H. et al. Combined inhibition of AURKA and HSF1 suppresses proliferation and promotes apoptosis in hepatocellular carcinoma by activating endoplasmic reticulum stress. Cell Oncol. 44, 1035–1049 (2021). https://doi.org/10.1007/s13402-021-00617-w

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  • DOI: https://doi.org/10.1007/s13402-021-00617-w

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