Catestatin peptide impedes melanoma progression and drug resistance by reprogramming oncogenic signaling pathways

Area of Science:

• Oncology
• Molecular Biology
• Peptide Therapeutics

Background:

• Melanoma is an aggressive, treatment-resistant cancer necessitating new therapeutic strategies.
• Catestatin (CST), a peptide derived from Chromogranin A (CgA), possesses immunomodulatory and skin repair properties.
• CST's role in melanoma carcinogenesis was previously unexplored, despite its presence in skin.

Purpose of the Study:

• To investigate the role of Catestatin (CST) in melanoma development and progression.
• To evaluate CST as a potential therapeutic agent against melanoma.
• To explore CST's efficacy in overcoming resistance to existing melanoma treatments.

Main Methods:

• Assessed CST expression in advancing melanoma stages.
• Administered CST to patient-derived cells and melanoma cell lines (A375, B16F10, SKMEL28).
• Evaluated CST's effect on melanoma cell apoptosis, proliferation, and metastasis in vitro and in vivo (B16F10 tumors).
• Conducted transcriptomic analyses of CST-treated cells and tumors.
• Tested CST's efficacy in Vemurafenib-resistant melanoma cells.

Main Results:

• Decreased CST expression correlated with advanced melanoma stages.
• CST treatment induced apoptosis, reduced proliferation, and inhibited metastasis in melanoma cells without harming normal fibroblasts.
• In vivo, CST significantly reduced tumor growth kinetics and weight.
• Transcriptomic analysis revealed CST downregulates hypoxia, collagen remodeling, epithelial-to-mesenchymal transition (EMT), and stress response pathways.
• CST enhanced apoptosis and repressed resistance genes in Vemurafenib-resistant melanoma cells.

Conclusions:

• Catestatin (CST) peptide demonstrates significant anti-melanoma activity.
• CST effectively targets key pathways driving melanoma progression and metastasis.
• CST shows potential as a therapeutic agent for melanoma, including overcoming resistance to targeted therapies.