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The natural product dehydrocurvularin induces apoptosis of gastric cancer cells by activating PARP-1 and caspase-3

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Abstract

The natural product dehydrocurvularin (DSE2) is a fungal-derived macrolide with potent anticancer activity, but the mechanism is still unclear. We found that DSE2 effectively inhibited the growth of gastric cancer cells and induced the apoptosis by activating Poly(ADP-ribose) polymerase 1 (PARP-1) and caspase-3. Pharmacological inhibition and genetic knockdown with PARP-1 or caspase-3 suppressed DSE2-induced apoptosis. PARP-1 was previously reported to be cleaved into fragments during apoptosis. However, PARP-1 was barely cleaved in DSE2-induced apoptosis. DSE2 induced PARP-1 activation as indicated by rapid depletion of NAD+ and the concomitant formation of poly(ADP-ribosylated) proteins (PARs). Interestingly, the PARP-1 inhibitor (Olaparib) attenuated the cytotoxicity of DSE2. Moreover, the combination of Olaparib and Z-DEVD-FMK (caspase-3 inhibitor) further reduced the cytotoxicity. It has been shown that PARP-1 activation triggers cytoplasm-nucleus translocation of apoptosis-inducing factor (AIF). Caspase-3 inhibitors inhibited PARP-1 activation and suppressed PARP-1-induced AIF nuclear translocation. These results indicated that DSE2-induced caspase-3 activation may occur before PARP-1 activation. The ROS inhibitor, N-acetyl-cysteine, significantly inhibited the activation of caspase-3 and PARP-1, indicating that ROS overproduction contributed to DSE2-induced apoptosis. Using an in vivo approach, we further found that DSE2 significantly inhibited gastric tumor growth and promoted translocation of AIF to the nucleus. In conclusion, DSE2 induces gastric cell apoptosis by activating caspase-3 and PARP-1, and shows potent antitumor activity against human gastric carcinoma in vitro and in vivo.

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Funding

This work was supported by National Key Research and Development Program of China (Grant numbers [2017YFD0201400]) and Changjiang Scholars and Innovative Research Team in University (Grant numbers [IRT_15R16]).

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Authors and Affiliations

  1. College of Life Science, Institute of Life Science and Green Development, Hebei University, 071002, Baoding, Hebei, China

    Huibin Xu, Xiaoman Shen, Xiangke Li, Xiaohui Yang, Chuan Chen & Duqiang Luo

  2. Key Laboratory of Microbial Diversity Research and Application of Hebei Province, Hebei University, 071002, Baoding, Hebei, China

    Chuan Chen

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  1. Huibin Xu
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by XH, SX and CC. Data curation and validation were performed by LX. Visualization and formal analysis were performed by YX. CC and LD conceived and supervised the study. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Chuan Chen or Duqiang Luo.

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The authors have no relevant financial or non-financial interests to disclose.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Animal Ethics and Welfare Committee of Hebei University (2020/IACUC-2020XS031).

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Xu, H., Shen, X., Li, X. et al. The natural product dehydrocurvularin induces apoptosis of gastric cancer cells by activating PARP-1 and caspase-3. Apoptosis 28, 525–538 (2023). https://doi.org/10.1007/s10495-023-01811-x

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