Tumor-suppressive effect of a telomerase-derived peptide

Abstract

Heat shock proteins (HSPs) are molecular chaperones that have critical roles in maintaining protein homeostasis

they are critical for cell survival especially under stresses such as hypoxia. HSPs, particularly HSP90 and HSP70, are highly expressed in a wide range of tumors. The expression of several HSPs has been shown to be correlated with tumor cell proliferation, differentiation and apoptosis in several cancers. A reverse-transcriptase subunit of telomerase (hTERT) derived peptide, GV1001 (Kael-GemVex Co. Ltd., Seoul, Korea) is a 16mer amino acid peptide, which was selected based on computer algorithms that predicted strong HLA class II binding properties encoded by multiple alleles from the HLA-DR, -DP, and ?DQ loci, thereby eliciting the T helper cell response in up to 80% of vaccinated patients and multiple nested HLA class I binding motifs. Subject to peptide processing by endogenous APCs, vaccination with GV1001 may thus recruit both CD4+ T cells and CD8+ cytotoxic T cells. Although GV1001 has been developed as a vaccine against various cancers, we have shown that GV1001 interacts with HSPs and lowers the level of intracellular and surface HSPs from various cancer cells. In hypoxic conditions, GV1001 treatment of cancer cells resulted in decreases of HSP90, HSP70, and HIF-1α. Subsequently, proliferation of cancer cells and synthesis of VEGF were significantly reduced by treatment with GV1001 in hypoxic conditions. In an experiment with a nude mouse xenograft model, GV1001 exerted a similar tumor suppressive effect, further confirming its anti-tumor efficacy. Higher apoptotic cell death, reduced proliferation of cells, and fewer blood vessels were observed in GV1001-treated tumors compared to the control. In addition, a significant decrease in Tie2+ CD11b+ monocytes, which were recruited by VEGF from tumor cells and have a critical role in angiogenesis, was observed in the GV1001-treated tumors. Collectively, the results suggest that GV1001 possesses potential therapeutic efficacy in addition to its ability to induce anti-cancer immune responses by suppressing both HSP70 and HSP90.