Inhibition of hepatocellular carcinoma growth by adenovirus-mediated expression of human telomerase reverse transcriptase COOH-27 terminal polypeptide in mice

Abstract

A 27-kDa C-terminal fragment of human telomerase reverse transcriptase, hTERTC27, has previously been reported to inhibit the growth and tumorigenicity of HeLa human cervical cancer cells and U87-MG human glioblastoma multiforme cells. However, the antitumor effects of hTERTC27 in hepatoma and its underlying mechanisms are unclear. In the current study, the therapeutic effect of hTERTC27, mediated by recombinant adenovirus, in hepatocellular carcinoma (HCC) was explored in vitro and in vivo to investigate the possible mechanisms. The results indicated that recombinant adenovirus carrying hTERTC27 (rAdv-hTERTC27) effectively inhibited the growth and induced apoptosis of the Hepa 1–6 HCC cells. Dendritic cells transduced with rAdv-hTERTC27 were highly effective at inducing antigen-specific T cell proliferation and increasing the activated cytotoxicity of T cells against Hepa 1–6 cells. HCC was inhibited significantly when a single dose of 5×107 pfu rAdv-hTERTC27 was administered intravenously. In summary, the results of this study demonstrated that rAdv-hTERTC27 may serve as a reagent for intravenous administration when combined with telomerase-based gene therapy and immunotherapy for cancer.

Long-term toxicity study of rAd5-hTERTC27 in SD rats and Cynomolgus monkeys by intravenous injection

“…A single dose of 5 Â 10 7 plaque-forming units (PFU) rAd5-hTERTC27 administered intravenously into mice also inhibited the growth of HCC significantly. Furthermore, we confirmed that both telomerase-based gene regulation and regulation of the immune system played important roles in the antitumor effect of hTERTC27 on HCC (He et al, 2013).…”

“…SD rats are advantageous because of their steady response to drugs, clear genetic background, and small individual variability, while Cynomolgus monkeys are extremely beneficial because they are physiologically similar to human beings. Having performed the initial, preclinical studies on the pharmacodynamics, safety pharmacology and acute toxicology of rAD5-hTERTC27 (He et al, 2013;Yue et al, 2013). We are now investigating its potential longer-term toxicological effects and immunogenicity following repeated intravenous dosing in rats and monkeys.…”

A multi-target protein of hTERTR-FAM96A presents significant anticancer potent in the treatment of hepatocellular carcinoma

“…10 Abdul-Ghani et al 11 reported that hTERT expressed in more than 80% of HCC cells and suggested that telomere elongation is a potential target of gene therapy for HCC. Previous study reported that adenovirus-mediated expression of hTERT COOH-27 terminal polypeptide inhibited HCC growth in mice 12 and overexpression of hTERTC27 also inhibited growth of HeLa cell and tumorigenicity in nude mouse xenografts. 13 In this study, we identified that human telomerase reverse transcriptase receptor (hTERTR) could interact with hTERT and disorder cellular metabolism of HCC cells.…”

Antitumor effect of COOH-terminal polypeptide of human TERT is associated with the declined expression of hTERT and NF-κB�p65 in HeLa�cells

“…Although the function of COOH terminus is the least-characterized, it has been found to mediate the nuclear translocation of telomerase (13) and is essential for the in vivo activity of human telomerase (14). Recent studies showed that ectopic expression of C27 (amino acid 882-1,132 of hTERT) reduces the growth and tumorigenicity of tumor cells (15)(16)(17)(18)(19) and sensitizes tumor cells to 5-fluorouracil-induced growth inhibition and apoptosis (20). C27 does not affect telomerase activity.…”

“…C27 does not affect telomerase activity. The unclearly illustrated mechanisms include the induction of telomere dysfunction (15), triggering of apoptosis signal and reduction of angiogenesis in tumor tissue (16), as well as involvement of immune responses (18).…”