Abstract
Cancer is a leading cause of mortality worldwide. Conventional chemotherapeutic agents for cancers do not distinguish between malignant and normal cells, leading to only limited success and high recurrence rates. Peptide-based treatments for cancer therapy have been of great interest and potential due to advantages including different regulation mechanisms, specific target to tumor cells, and low toxicity in normal tissues. A sulfated GAG-binding peptide (GBPHH) derived from core heparan sulfate (HS) binding motif of human eosinophil cationic protein (hECP) has been recently identified to have anti-tumor functions. In this study GBPHH and 3 derivates (GBPHH(C6S), GBPHL and GBPLL) with variation in only 1 out of 10 amino acids in sequence displayed distinct binding and penetrating activities toward epithelial cancer cells. Interestingly, migration and invasion activities of epithelial cancer cells were significantly inhibited by GBPHH with higher binding and the highest penetration activities, so as GBPHH(C6S). However, GBPHL with the highest binding and lower penetration activities and GBPLL with the lowest binding and penetration activities showed much weaker inhibitory effects. As for molecular mechanisms, phosphorylation of migration-associated molecules decreased upon treatment with GBPHH. GBPHH as a novel metastatic suppressor which acts through initial GAG binding and cell penetration, involved in modulation of cellular signals of epithelial cancer cells. Understanding sequence dependence and anti-tumor mechanisms of GBPHH provides alternative strategies to design more efficacious peptides, synthesize chemically modified drugs, and develop novel formulation and delivery system of GBPHH-based drugs for anti-epithelial cancer.