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Ganoderma immunomodulatory protein and chidamide down-regulate integrin-related signaling pathway result in migration
Chun-Te Lu1, Pui-Ying Leong2, Ting-Yi Hou3
1Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Division of Plastic and Reconstructive Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.
Background:
In terms of melanoma, recent advances have been made in target therapies and immune checkpoint inhibitors, but durable remission is rare. Ganoderma immunomodulatory proteins (GMI) induce a cytotoxic effect in cancer cells via autophagy. However, the role of GMI in melanoma is not clear.
Purpose:
The aims of this study are to investigate the inhibiting effects of GMI combined with chidamide on survival and metastases of melanoma cells via integrin-related signaling pathway and to propose strategies for combining GMI and chidamide using animal model.
Methods:
Cell viability was measured by cell CCK-8. The activities of apoptosis- and migration-related proteins were detected on Western blot. Flow cytometry was used to analyze cell cycle distribution and sub-G1 fraction in treated melanoma cells. To evaluate the activity of combination GMI and chidamide treatment, an in vivo anti-tumor metastasis study was performed.
Results:
GMI combined with chidamide additively induced apoptosis. GMI inhibited the expressions of Integrin α5, αV, β1, and β3. The level of p-FAK was inhibited by GMI. Combination treatment of GMI and chidamide decreased survivin and increased cleaved caspase-7 and LC3 II/I. Integrin-αV overexpression activated p-FAK pathways in A375.S2 cells. GMI significantly inhibited cell growth and migration of A375.S2 cells on wound healing assay. In vivo, GMI combined with chidamide suppressed distal tumor metastasis.
Conclusion:
GMI inhibits the migration and growth of melanoma cells via integrin-related signaling pathway. GMI and chidamide induces apoptosis. In vivo, GMI and chidamide additively reduce distant metastases. GMI and chidamide are potential immunotherapeutic adjuvant for metastatic melanoma.
Insights
Ganoderma immunomodulatory proteins (GMI) and chidamide inhibit melanoma growth and metastasis by targeting the integrin pathway. This combination therapy shows promise for treating metastatic melanoma.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Durable remission in melanoma remains challenging despite advances in targeted therapies and immune checkpoint inhibitors.
- Ganoderma immunomodulatory proteins (GMI) exhibit cytotoxic effects on cancer cells through autophagy, but their role in melanoma is not fully understood.
Purpose of the Study:
- To investigate the combined inhibitory effects of GMI and chidamide on melanoma cell survival and metastasis.
- To elucidate the role of the integrin-related signaling pathway in GMI and chidamide's anti-melanoma activity.
- To propose therapeutic strategies for combining GMI and chidamide in a preclinical animal model.
Main Methods:
- Cell viability assessed using CCK-8 assays.
- Apoptosis and migration-related protein expression analyzed via Western blot.
- Cell cycle distribution and sub-G1 fraction determined by flow cytometry.
- In vivo anti-tumor metastasis studies conducted to evaluate combination treatment efficacy.
Main Results:
- GMI and chidamide synergistically induced apoptosis and reduced survivin levels.
- GMI inhibited key integrin subunits (α5, αV, β1, β3) and downstream p-FAK signaling.
- Combination treatment increased cleaved caspase-7 and LC3 II/I ratios, indicating enhanced apoptosis and autophagy.
- GMI suppressed melanoma cell growth and migration in vitro, while the combination therapy inhibited distal tumor metastasis in vivo.
Conclusions:
- GMI effectively inhibits melanoma cell migration and growth by modulating the integrin-related signaling pathway.
- Combined GMI and chidamide treatment induces apoptosis and additively reduces distant metastases in vivo.
- GMI and chidamide represent a potential immunotherapeutic adjuvant strategy for managing metastatic melanoma.
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