Anticancer therapy against hepatocellular carcinoma by survivin targeting

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Survivin, which is expressed in cancer tissues including hepatocellular carcinoma but not in normal tissues, represses the activities of caspases resulting in resistance of cancer cells to Fas- or chemotherapeutic agent-mediated apoptosis. In addition, inhibition of survivin expression, by transduction with anti-sense oligonucleotides or a dominant-negative expression vehicle, sensitized cancer cells to chemotherapeutic agent-mediated apoptosis. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in a variety of cancer cells with little or no effect on normal cells. Human hepatoma cells, however, are resistant to TRAIL-induced apoptosis. Recently, Griffith et al. reported that the cellular level of survivin is closely relevant to the resistance against TRAIL-mediated apoptosis of renal cell carcinoma cells. In the present study, we have shown that the preincubation with 1,000 IU of IFN-α apparently enhanced the TRAIL-induced apoptosis in HuH-7, Hep3B and PLC/PRF/5 human hepatoma cells. The expression of survivin as well as its m-RNA was repressed by IFN-α in these cells. We also demonstrated that ectopic expression of survivin significantly repressed the TRAIL/IFN-α -induced apoptosis of HuH-7 cells. These findings suggest that downregulation of survivin by IFN-α may account for the enhancement of TRAIL-mediated apoptosis by IFN-α, and that TRAIL in combination with IFN-α may have therapeutic potential in the treatment of human hepatocellular carcinoma.We also found that down regulation of surviving expression by siRNA transfection sensitized human hepatoma cells to TRAIL-induced apoptosis.