Background & Aims:Human LPTS is a liver-related, putative tumor suppressor gene that encodes a telomerase inhibitory protein that is similar to human PinX1. The LPTS protein binds directly to the telomerase catalytic subunit (hTERT) and suppresses telomerase activity. Telomere maintenance and telomerase activity are required for long-term proliferation of cancer cells, so LPTS might be used in anti-cancer strategies.Methods:The carboxy-terminal (functional) fragment of LPTS was fused to HIV Tat—an 11 amino acid peptide that translocates across the cell membrane; the fusion protein (TAT–LPTS-LC) was purified and transduced into cells. Telomerase activity was identified by using the telomeric repeat amplification protocol. The effects of the TAT–LPTS-LC protein on cell proliferation and death were evaluated by MTT and flow cytometry analyses. Tumor growth was analyzed in nude mice.Results:The purified TAT–LPTS-LC protein was efficiently delivered into the cells, where it suppressed telomerase activity and shortened telomere length. TAT–LPTS-LC inhibited proliferation of telomerase-positive hepatocellular carcinoma BEL-7404 and hepatoblastoma HepG2cells and induced their death; however, it had no effects on telomerase-negative liver cell line L02 and osteosarcoma cell line Saos-2. In mice, tumor formations by BEL-7404 cells were suppressed by TAT-LPTS-LC treatments.Conclusions:Transduction of hepatoma cells with a fusion protein that contains the C-terminal, functional fragment of LPTS and HIV Tat (TAT–LPTS-LC) causes telomere shortening, limits proliferation, and inhibits growth of tumors from these cells in mice. TAT–LPTS-LC inhibits telomerase activity and might be developed as anti-cancer agent.