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Caerin 1.1/1.9 interfere KHDRBS1-DDX5 regulatory axis to induce IL-18 mediated pyroptosis in a HeLa cell tumour model
Mengqi Liu1, Yuandong Luo2, Xinyi Song3
1Medical School, Guizhou University, Guiyang, 550025, Guizhou Province, China.
Abstract:
Cervical cancer remains a significant global health challenge, particularly in developing countries where access to HPV vaccination is limited. We previously demonstrated that caerin 1.1/1.9 (F1F3) peptides inhibit tumour growth in vitro and in vivo by inducing pyroptosis, followed by apoptosis and immune activation. In this study, we elucidate the molecular mechanisms underlying F1F3-induced pyroptosis in HeLa cells. Our results show that F1F3 triggers pyroptosis independently of GSDME, as evidenced by comparable IL-18 and LDH release in both wild type and GSDME knockout cells. Cross-linking mass spectrometry identified the interaction of F1 to KHDRBS1 and F3 to DDX5, respectively. Knockout of either KHDRBS1 or DDX5 enhanced HeLa cell sensitivity to F1F3 and significantly elevated IL-18 secretion. Notably, KHDRBS1-deficint tumours displayed accelerated growth yet responded more robustly to F1F3 treatment, suggesting a context-dependent tumour-suppressive role of KHDRBS1. These findings uncover a previously uncharacterised pathway regulated by KHDRBS1-DDX5 and demonstrate that F1F3 can effectively interfere with this axis to induce anti-tumour immune responses, highlighting their potential as novel therapeutic agents for cervical cancer.
Insights
Caerulein peptides (F1F3) trigger pyroptosis in cervical cancer cells independently of GSDME. This mechanism involves KHDRBS1 and DDX5, offering potential for new cervical cancer therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cervical cancer poses a significant global health burden, especially where HPV vaccination is limited.
- Caerulein 1.1/1.9 (F1F3) peptides show promise in inhibiting tumor growth via pyroptosis, apoptosis, and immune activation.
Purpose of the Study:
- To elucidate the molecular mechanisms of F1F3-induced pyroptosis in cervical cancer (HeLa) cells.
- To identify specific protein interactions and pathways targeted by F1F3 peptides.
Main Methods:
- Utilized GSDME knockout HeLa cells to assess pyroptosis pathways.
- Employed cross-linking mass spectrometry to identify protein interactions.
- Investigated the role of KHDRBS1 and DDX5 in F1F3-mediated cell death and immune response.
Main Results:
- F1F3-induced pyroptosis occurs independently of GSDME, with similar IL-18 and LDH release in wild-type and knockout cells.
- F1F3 peptides interact with KHDRBS1 (F1) and DDX5 (F3).
- Knockout of KHDRBS1 or DDX5 increases F1F3 sensitivity and IL-18 secretion; KHDRBS1-deficient tumors show enhanced F1F3 response.
Conclusions:
- F1F3 peptides induce pyroptosis through a novel KHDRBS1-DDX5 pathway, independent of GSDME.
- Targeting the KHDRBS1-DDX5 axis with F1F3 peptides can stimulate anti-tumor immune responses.
- F1F3 peptides represent potential novel therapeutic agents for cervical cancer treatment.
