hTERT peptide fragment GV1001 demonstrates radioprotective and antifibrotic effects through suppression of TGF- signaling

摘要

GV1001 is a 16-amino acid peptide derived from the human telomerase reverse transcriptase (hTERT) protein (616-626; EARPALLTSRLRFIPK), which lies within the reverse transcriptase domain. Originally developed as an anticancer vaccine, GV1001 demonstrates diverse cellular effects, including anti-inflammatory, tumor suppressive and antiviral effects. In the present study, the radioprotective and antifibrotic effects of GV1001 were demonstrated through suppressing transforming growth factor- (TGF-) signaling. Proliferating human keratinocytes underwent premature senescence upon exposure to ionizing radiation (IR), however, treatment of cells with GV1001 allowed the cells to proliferate and showed a reduction in senescent phenotype. GV1001 treatment notably increased the levels of Grainyhead-like 2 and phosphorylated (p-)Akt (Ser473), and reduced the activation of p53 and the level of p21/WAF1 in irradiated keratinocytes. It also markedly suppressed the level of TGF- signaling molecules, including p-small mothers against decapentaplegic (Smad)2/3 and Smad4, and TGF- target genes, including zinc finger E-box binding homeobox 1, fibronectin, N-cadharin and Snail, in irradiated keratinocytes. Furthermore, GV1001 suppressed TGF- signaling in primary human fibroblasts and inhibited myofibroblast differentiation. Chromatin immunoprecipitation revealed that GV1001 suppressed the binding of Smad2 on the promoter regions of collagen type III 1 chain (Col3a1) and Col1a1. In a dermal fibrosis model in vivo, GV1001 treatment notably reduced the thickness of fibrotic lesions and the synthesis of Col3a1. These data indicated that GV1001 ameliorated the IR-induced senescence phenotype and tissue fibrosis by inhibiting TGF- signaling and may have therapeutic effects on radiation-induced tissue damage.