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Hesperadin suppresses pancreatic cancer through ATF4/GADD45A axis at nanomolar concentrations

Oncogene volume 41, pages 3394–3408 (2022)Cite this article

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Abstract

Pancreatic cancer (PC) is a fatal disease with poor survival and limited therapeutic strategies. In this study, we identified Hesperadin as a potent anti-cancer compound against PC, from a high-throughput screening of a commercial chemical library associated with cell death. Hesperadin induced potent growth inhibition in PC cell lines and patient-derived tumor organoids in a dose- and time-dependent manner, with IC50 values in the nanomolar range. Cellular studies showed that Hesperadin caused mitochondria damage in PC cells, resulting in reactive oxygen species production, ER stress and apoptotic cell death. Transcriptomic analysis using RNA-sequencing data identified GADD45A as a potential target of Hesperadin. Mechanistic studies showed that Hesperadin could increase GADD45A expression in PC cells via ATF4, leading to apoptosis. Moreover, immunohistochemical staining of 92 PC patient samples demonstrated the correlation between ATF4 and GADD45A expression. PC xenograft studies demonstrated that Hesperadin could effectively inhibit the growth of PC cells in vivo. Together, these findings suggest that Hesperadin is a novel drug candidate for PC.

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Fig. 1: Identification of Hesperadin as a novel anti-cancer agent against PC.
Fig. 2: Hesperadin induces mitochondrial dysfunction and ROS accumulation.
Fig. 3: Hesperadin leads to cell death via ER stress.
Fig. 4: ROS are critical in ER stress-induced cell death.
Fig. 5: Hesperadin leads to PC cells death via ATF4/GADD45A axis.
Fig. 6: Hesperadin inhibits the proliferation of PC organoids.
Fig. 7: Hesperadin inhibits xenograft tumor growth in vivo.
Fig. 8: Schematic of the anti-tumor effects of Hesperadin in PC cells.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81802396 and 82072652), Natural Science Foundation of Jiangsu Province (SBK2019022491 and BK20180117), General Project of Nanjing Medical Science and Technology Development Project (YKK17077), Nanjing Science and Technology Development Plan Project (201715023), Nanjing Medical Science and Technology Development Key Project (ZKX18022), and Nanjing Science and technology project (201911038).

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  1. These authors contributed equally: Yixuan Zhang, Jianzhuang Wu, Yao Fu.

Authors and Affiliations

  1. Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China

    Yixuan Zhang, Hao Wu, Jing Zhao, Shanshan Shen, Guifang Xu, Lei Wang, Xiaoping Zou, Ying Lv & Shu Zhang

  2. Nanjing University Institute of Pancreatology, Nanjing, China

    Yixuan Zhang, Jianzhuang Wu, Haochen Su, Hao Wu, Siqi Zhou, Kun Wang, Jing Zhao, Shanshan Shen, Guifang Xu, Lei Wang, Chao Yan, Xiaoping Zou, Ying Lv & Shu Zhang

  3. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China

    Jianzhuang Wu, Ranran Yu & Chao Yan

  4. Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China

    Yao Fu

  5. Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Haochen Su

  6. Department of Clinical Laboratory, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China

    Qisi Zheng

  7. Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Jiangsu University, Nanjing, China

    Siqi Zhou

  8. Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Xuzhou Medical University, Nanjing, China

    Kun Wang

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Contributions

SZ, YL and XPZ conceived and designed the study. YXZ, JZW and YF performed the experiments and interpreted the data. RRY analyzed the sequencing results. HCS, QSZ and HW assisted in animal experiments. SQZ, KW and JZ assisted in collecting tissue samples. SSS and GFX assisted in analyzing data. LW and CY revised the manuscript.

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Correspondence to Xiaoping Zou, Ying Lv or Shu Zhang.

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Zhang, Y., Wu, J., Fu, Y. et al. Hesperadin suppresses pancreatic cancer through ATF4/GADD45A axis at nanomolar concentrations. Oncogene 41, 3394–3408 (2022). https://doi.org/10.1038/s41388-022-02328-4

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