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Hesperadin suppresses pancreatic cancer through ATF4/GADD45A axis at nanomolar concentrations
Yixuan Zhang1,2, Jianzhuang Wu2,3, Yao Fu4
1Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.
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.
Insights
Hesperadin effectively inhibits pancreatic cancer (PC) growth by inducing cell death. This compound shows promise as a novel therapeutic drug candidate for treating pancreatic cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Pancreatic cancer (PC) presents a significant global health challenge with limited effective treatment options.
- There is an urgent need for novel therapeutic strategies to improve patient survival rates in PC.
Purpose of the Study:
- To identify and characterize novel anti-cancer compounds for pancreatic cancer treatment.
- To investigate the mechanism of action of Hesperadin in PC cells and its therapeutic potential.
Main Methods:
- High-throughput screening of a chemical library to identify anti-cancer compounds.
- In vitro studies using PC cell lines and patient-derived tumor organoids.
- Cellular assays to assess mitochondrial damage, reactive oxygen species production, ER stress, and apoptosis.
- RNA-sequencing for transcriptomic analysis and identification of molecular targets.
- In vivo studies using PC xenograft models.
Main Results:
- Hesperadin demonstrated potent dose- and time-dependent growth inhibition of PC cells and organoids (nanomolar IC50 values).
- Hesperadin induced mitochondrial damage, reactive oxygen species production, ER stress, and apoptotic cell death in PC cells.
- Transcriptomic analysis identified GADD45A as a target, with Hesperadin increasing its expression via ATF4, leading to apoptosis.
- Correlation between ATF4 and GADD45A expression was observed in patient samples.
- Hesperadin significantly inhibited PC tumor growth in vivo.
Conclusions:
- Hesperadin is a potent anti-cancer compound effective against pancreatic cancer in vitro and in vivo.
- Hesperadin induces PC cell death through mitochondrial damage and the ATF4/GADD45A pathway.
- Hesperadin represents a promising novel drug candidate for the treatment of pancreatic cancer.
