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Pentagamavunone-1 targets excessive MYCN/NCYM expression mediated by mitotic arrest to suppress hepatocellular carcinoma proliferation

Cancer Gene Therapy (2025)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is a common liver cancer often diagnosed at an advanced stage. While chemotherapies such as sorafenib is effective for some patients, others show poor responses, necessitating new treatments. Overexpression of MYCN/NCYM was recently shown to contribute to the development of HCC. This study investigated the effects of Pentagamavunone-1 (PGV-1), a curcumin analog with strong antiproliferative properties, on HCC cells expressing MYCN/NCYM. PGV-1 was more effective than curcumin and sorafenib in inhibiting HCC cell proliferation by inducing mitotic arrest, oxidative stress, and senescence. In MYCN-positive JHH-7 cells, PGV-1 treatment increased phosphorylation of aurora A, cyclin B1, and PLK1. PGV-1 also suppressed MYCN/NCYM transcription and destabilized MYCN protein by inducing phosphorylation at Ser54 and Thr58. In a xenograft model, PGV-1 significantly reduced tumor formation and growth. These findings highlight PGV-1’s potential as a targeted therapy for MYCN-overexpressing HCC, warranting further development.

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Fig. 1: Antiproliferative effects of PGV-1 in human hepatocellular carcinoma (HCC) cells.
Fig. 2: PGV-1 irreversibly inhibits JHH-7 cell growth.
Fig. 3: PGV-1 halts cell cycle progression in mitosis and induces cellular senescence.
Fig. 4: PGV-1 induces the phosphorylation of major kinases PLK1, aurora A, and cyclin B1 following prometaphase arrest.
Fig. 5: Pentagamavunone-1 suppresses MYCN/NCYM mRNA expression and accelerates the degradation of the MYCN oncoprotein by promoting the phosphorylation of Thr58 and Ser54.
Fig. 6: Pentagamavunone-1 inhibits HCC xenograft tumors in vivo.
Fig. 7: Pentagamavunone-1 inhibits HCC xenograft tumors in vivo.

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All data generated or analyzed during the present study are included in the article and its supplementary information files.

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Acknowledgements

We thank Drs. Yoshitaka Hippo and Yusuke Suenaga in the Chiba Cancer Center for their discussions and suggestions, Michiyo Ueno for her technical assistance, and the staff in the Life Science Collaboration Center (LiSCo), NAIST for the support in conducting animal experiments. This research was supported by AMED under Grant Number JP23jm0210092, by JSPS KAKENHI Grant Number JP25K10492 and by the Iida Scholarship Foundation.

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Authors and Affiliations

  1. Laboratory of Tumor Cell Biology, Institute for Research Initiatives, Nara Institute of Science and Technology, Nara, Japan

    Dhania Novitasari, Ikuko Nakamae, Noriko Yoneda-Kato & Jun-ya Kato

  2. Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, Indonesia

    Dhania Novitasari

  3. Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia

    Dhania Novitasari & Edy Meiyanto

  4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia

    Edy Meiyanto

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Contributions

DN, EM, and JyK designed the experiments. DN, IN, and JyK performed the experiments. DN, IN, NYK, EM, and JyK analyzed the data. DN and JyK wrote the manuscript. DN, NYK, EM, and JyK edited the manuscript.

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Correspondence to Jun-ya Kato.

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The authors declare no competing interests.

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All methods were performed in accordance with NAIST guidelines and regulations. The experimental protocols used in the present study were approved by the NAIST Institutional and Licensing Committees (reference number 1805). The study is reported in accordance with ARRIVE guidelines.

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Novitasari, D., Nakamae, I., Yoneda-Kato, N. et al. Pentagamavunone-1 targets excessive MYCN/NCYM expression mediated by mitotic arrest to suppress hepatocellular carcinoma proliferation. Cancer Gene Ther (2025). https://doi.org/10.1038/s41417-025-00956-y

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