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Targeting PRSS23 with tipranavir induces gastric cancer stem cell apoptosis and inhibits growth of gastric cancer via the MKK3/p38 MAPK-IL24 pathway

Acta Pharmacologica Sinica volume 45, pages 405–421 (2024)Cite this article

Abstract

Gastric cancer stem cells (GCSCs) contribute to the refractory features of gastric cancer (GC) and are responsible for metastasis, relapse, and drug resistance. The key factors drive GCSC function and affect the clinical outcome of GC patients remain poorly understood. PRSS23 is a novel serine protease that is significantly up-regulated in several types of cancers and cancer stem cells, and related to tumor progression and drug resistance. In this study, we investigated the role of PRSS23 in GCSCs as well as the mechanism by which PRSS23 regulated the GCSC functions. We demonstrated that PRSS23 was critical for sustaining GCSC survival. By screening a collection of human immunodeficiency virus (HIV) protease inhibitors (PIs), we identified tipranavir as a PRSS23-targeting drug, which effectively killed both GCSC and GC cell lines (its IC50 values were 4.7 and 6.4 μM in GCSC1 cells and GCSC2 cells, respectively). Administration of tipranavir (25 mg·kg−1·d−1, i.p., for 8 days) in GCSC-derived xenograft mice markedly inhibited the growth of subcutaneous GCSC tumors without apparent toxicity. In contrast, combined treatment with 5-FU plus cisplatin did not affect the tumor growth but causing significant weight loss. Furthermore, we revealed that tipranavir induced GCSC cell apoptosis by suppressing PRSS23 expression, releasing MKK3 from the PRSS23/MKK3 complex to activate p38 MAPK, and thereby activating the IL24-mediated Bax/Bak mitochondrial apoptotic pathway. In addition, tipranavir was found to kill other types of cancer cell lines and drug-resistant cell lines. Collectively, this study demonstrates that by targeting both GCSCs and GC cells, tipranavir is a promising anti-cancer drug, and the clinical development of tipranavir or other drugs specifically targeting the PRSS23/MKK3/p38MAPK-IL24 mitochondrial apoptotic pathway may offer an effective approach to combat gastric and other cancers.

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Fig. 1: Overexpression of PRSS23 is essential for the survival of GCSCs.
Fig. 2: Tipranavir reduces the viability of both GCSCs and GC cell lines.
Fig. 3: Tipranavir-induced GCSC and GC death are dependent on PRSS23.
Fig. 4: Tipranavir induces apoptosis of GCSCs via the mitochondrial pathway.
Fig. 5: Tipranavir promotes GCSC apoptosis by inducing IL24 expression.
Fig. 6: The PRSS23/MKK3/p38 MAPK pathway activates the IL24-dependent mitochondrial apoptotic pathway in GCSCs.
Fig. 7: Tipranavir inhibits GCSC-derived tumor growth without apparent toxicity.
Fig. 8: The proposed mechanism by which tipranavir induces GCSC apoptosis.

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Data availability

Sequencing data from the RNA-seq experiments are available on the GEO server (GSE210249 and GSE161825). The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We acknowledge Dr. Xian-ming Mo (Sichuan University) for providing the GCSC cells. We thank Dr. Xiang-wei Wang and Dr. Yu-qi Wu (Shenzhen University General Hospital) for providing the PC3/Tax cells. We also thank Dr. Wen Su (Shenzhen University) for help in histological examination. This work was supported by grants from the National Natural Science Foundation of China (82173003), the Science and Technology Foundation of Shenzhen (JCYJ20200109113810154), the Science and Technology Program of Guangdong Province in China (2019B030301009), the Industry and Information Technology Foundation of Shenzhen (20180309100135860), the SZU Top Ranking Project (86000000210) and the Guangdong Basic and Applied Basic Research Foundation (2020A1515010989 and 2018A030310586).

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Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China

    Ji-xian Xiong, Yu-ting Li, Xiang-yu Tan & Li Fu

  2. School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China

    Tie Chen

  3. Department of Biochemistry, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China

    Bao-hua Liu

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Contributions

Conceptualization: JXX and LF; methodology: JXX, YTL, XYT, and LF; investigation: JXX, YTL, XYT, and TC; writing: JXX and LF; funding acquisition: JXX and LF; resources: BHL; supervision: JXX and LF.

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Correspondence to Ji-xian Xiong or Li Fu.

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Xiong, Jx., Li, Yt., Tan, Xy. et al. Targeting PRSS23 with tipranavir induces gastric cancer stem cell apoptosis and inhibits growth of gastric cancer via the MKK3/p38 MAPK-IL24 pathway. Acta Pharmacol Sin 45, 405–421 (2024). https://doi.org/10.1038/s41401-023-01165-9

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