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Betulinic acid induces apoptosis of HeLa cells via ROS-dependent ER stress and autophagy in vitro and in vivo

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Abstract

Betulinic acid (BA), a naturally occurring lupane-type triterpenoid, possesses a wide range of potential activities against different types of cancer. However, the molecular mechanisms involved in anti-cervical cancer about BA were rarely investigated. Herein, the role of BA in cervical cancer suppression by ROS-mediated endoplasmic reticulum stress (ERS) and autophagy was deeply discussed. The findings revealed that BA activated Keap1/Nrf2 pathway and triggered mitochondria-dependent apoptosis due to ROS production. Furthermore, BA increased the intracellular Ca2+ levels, inhibited the expression of Beclin1 and promoted the expression of GRP78, LC3-II, and p62 associated with ERS and autophagy. Besides, BA initiated the formation of autophagosomes and inhibited autophagic flux by the co-administration of BA with 3-methyladenine (3-MA) and chloroquine (CQ), respectively. The in vivo experiment manifested that hydroxychloroquine (HCQ) enhanced the apoptosis induced by BA. For the first time, we demonstrated that BA could initiate early autophagy, inhibit autophagy flux, and induce protective autophagy in HeLa cells. Thus, BA could be a potential chemotherapy drug for cervical cancer, and inhibition of autophagy could enhance the anti-tumor effect of BA. However, the interactions of signaling factors between ERS-mediated and autophagy-mediated apoptosis deserve further attention.

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Funding

This work was supported by the National Natural Science Foundation of China (82073986).

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  1. Ping Chen and Xueer Zhang have contributed equally to this work.

Authors and Affiliations

  1. School of Pharmaceutical Sciences, GuangZhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China

    Ping Chen, Xueer Zhang, Qiaomiao Fang, Zhongxiang Zhao, Chaozhan Lin, Yuan Zhou, Fangle Liu, Chenchen Zhu & Aizhi Wu

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  1. Ping Chen
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  2. Xueer Zhang
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Contributions

CP carried out bioassays and prepared the manuscript; ZXE performed the isolation of the compounds and prepared the manuscript; FQM carried out the MTT assay; ZZX and LCZ round off the manuscript; LFL and ZY provided the technical guidance; ZCC directed the project administration and funding acquisition; WAZ conceived and directed this investigation. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Aizhi Wu.

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Chen, P., Zhang, X., Fang, Q. et al. Betulinic acid induces apoptosis of HeLa cells via ROS-dependent ER stress and autophagy in vitro and in vivo. J Nat Med (2024). https://doi.org/10.1007/s11418-024-01782-6

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