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Secukinumab plays a synergistic role with starvation therapy in promoting autophagic cell death of hepatocellular carcinoma via inhibiting IL-17A-increased BCL2 level

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Abstract

It is known that IL-17A inhibits autophagy of hepatocellular carcinoma (HCC) cells, thus contributing to the carcinogenesis of HCC. Starvation therapy can promote the autophagic death of HCC cells by blocking the nutrition supply. The purpose of this study was to explore whether the pharmacological antagonist of IL-17A, secukinumab, and starvation therapy have a synergistic effect on the autophagic cell death of HCC. Here, it could be observed that compared with serum-free condition, the combination of secukinumab and serum-free status better promoted autophagy (observed by LC3 conversion rate, p62 protein expression and the formation of autophagosomes), and more significantly inhibited the survival and function (observed by Trypan blue staining, CCK-8, Transwell, and scratch assays) in HCC HepG2 cells. Moreover, secukinumab significantly decreased BCL2 protein expression under serum-normal and serum-free conditions. However, both the addition of recombinant IL-17A and overexpression of BCL2 blocked the regulation of secukinumab on the survival and autophagy in HepG2 cells. Nude mice experiments demonstrated that compared to the lenvatinib-alone group, the combination group of lenvatinib and secukinumab better inhibited the in vivo tumorigenesis of HepG2 cells and enhanced autophagy in xenotumor tissues. Furthermore, secukinumab significantly decreased BCL2 protein expression in xenotumor tissues without or with lenvatinib application. In conclusion, the antagonism of IL-17A with secukinumab, due to the upregulation on BCL2-related autophagic cell death, can cooperate with starvation therapy in inhibiting HCC carcinogenesis. Our data suggested that secukinumab can become an effective adjuvant for the treatment of HCC.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the Provincial Natural Science Foundation of China Hainan (819MS119) and the Natural Science Foundation of Hainan General Hospital (QN202011).

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Authors and Affiliations

  1. Department of Hepatopancreatobiliary Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, HuaXiu Road 19th, Haikou, 570311, Hainan, China

    Rong Tang, Jinfang Zheng, Jincai Wu, Pingping Chen, Jiacheng Chen, Dafeng Xu, Yongchao Zeng, Qijin Li & Zhensheng Zhang

  2. Department of Obstetrics, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, China

    Linmei Zheng

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  1. Rong Tang
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  2. Linmei Zheng
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  3. Jinfang Zheng
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  6. Jiacheng Chen
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  10. Zhensheng Zhang
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Contributions

Zhensheng Zhang and Rong Tang conceived and designed the experiments; Rong Tang, Linmei Zheng, Jinfang Zheng, Jincai Wu, and Pingping Chen performed the experiments, analyzed the data, and prepared the figures; Jiacheng Chen, Dafeng Xu, Yongchao Zeng, and Qijin Li assisted in data analysis; Zhensheng Zhang and Rong Tang wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Zhensheng Zhang.

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Rong Tang and Linmei Zheng are considered co-first authors.

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Tang, R., Zheng, L., Zheng, J. et al. Secukinumab plays a synergistic role with starvation therapy in promoting autophagic cell death of hepatocellular carcinoma via inhibiting IL-17A-increased BCL2 level. In Vitro Cell.Dev.Biol.-Animal 59, 381–393 (2023). https://doi.org/10.1007/s11626-023-00770-6

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