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Vismodegib Potentiates Marine Antimicrobial Peptide Tilapia Piscidin 4-Induced Cytotoxicity in Human Non-Small Cell Lung Cancer Cells

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Abstract

Non-small cell lung cancer (NSCLC) is a common cancer with several accepted treatments, such as chemotherapy, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, and immune checkpoint inhibitors. Nevertheless, NSCLC cells often become insensitive to these treatments, and therapeutic resistance is a major reason NSCLC still has a high mortality rate. The induction of therapeutic resistance in NSCLC often involves hedgehog, and suppression of hedgehog can increase NSCLC cell sensitivity to several conventional therapies. In our previous work, we demonstrated that the marine antimicrobial peptide tilapia piscidin 4 (TP4) exhibits potent anti-NSCLC activity in both EGFR-WT and EGFR-mutant NSCLC cells. Here, we sought to further explore whether hedgehog might influence the sensitivity of NSCLC cells to TP4. Our results showed that hedgehog was activated by TP4 in both WT and EGFR-mutant NSCLC cells and that pharmacological inhibition of hedgehog by vismodegib, a Food and Drug Administration-approved hedgehog inhibitor, potentiated TP4-induced cytotoxicity. Mechanistically, vismodegib acted by enhancing TP4-mediated increases in mitochondrial membrane potential and intracellular reactive oxygen species (ROS). MitoTempo, a specific mitochondrial ROS scavenger, abolished vismodegib/TP4 cytotoxicity. The combination of vismodegib with TP4 also reduced the levels of the antioxidant proteins catalase and superoxide dismutase, and it diminished the levels of chemoresistance-related proteins, Bcl-2 and p21. Thus, we conclude that hedgehog regulates the cytotoxic sensitivity of NSCLC cells to TP4 by protecting against mitochondrial dysfunction and suppressing oxidative stress. These findings suggest that combined treatment of vismodegib and TP4 may be a promising therapeutic strategy for NSCLC.

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Acknowledgements

We thank Marcus Calkins for language editing.

Funding

This research was funded by the Ministry of Science and Technology (MOST; Taiwan), MOST 109-2320-B-038-010-MY2; 110-2320-B-038 -023. This research was also funded by Taipei Municipal Wan Fang Hospital, 110TMU-WFH-20.

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Author notes

  1. Wei-Chen Yeh and Yun-Chieh Tu are equally contributed to this work.

Authors and Affiliations

  1. School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Wei-Chen Yeh, Yun-Chieh Tu & Tzu-Cheng Chien

  2. Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan

    Pei-Ling Hsu

  3. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan

    Pei-Ling Hsu

  4. Department of Nursing, National Tainan Junior College of Nursing, 78, Section 2, Minzu Road, West Central District, Tainan, 70007, Taiwan

    Chu-Wan Lee

  5. Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC, 27157, USA

    Shih-Ying Wu

  6. Department of Pathology, Duke University School of Medicine, Durham, NC27710, USA

    Bo-Syong Pan

  7. Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Hsin-Hsien Yu

  8. Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Hsin-Hsien Yu

  9. Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Bor-Chyuan Su

  10. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Bor-Chyuan Su

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Contributions

W.C.Y, Y.C.T, T.C.C., P.L.H, and C.W.L. conducted experiments. W.C.Y., Y.C.T., S.Y.W., B.S.P., and H.H.Y. evaluated data. B.C.S. conceived, designed the research, wrote, and revised the manuscript. B.C.S. supervised the experiments. All authors read and approved the manuscript.

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Yeh, WC., Tu, YC., Chien, TC. et al. Vismodegib Potentiates Marine Antimicrobial Peptide Tilapia Piscidin 4-Induced Cytotoxicity in Human Non-Small Cell Lung Cancer Cells. Probiotics & Antimicro. Prot. (2024). https://doi.org/10.1007/s12602-024-10282-8

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