Hepatocellular Carcinoma Repression By Tnf Alpha-Mediated Synergistic Lethal Effect Of Mitosis Defect-Induced Senescence And Cell Death Sensitization

Hepatocellular carcinoma (HCC) is a cancer lacking effective therapies. Several measures have been proposed to treat HCCs, such as senescence induction, mitotic inhibition, and cell death promotion. However, data from other cancers suggest that single use of these approaches may not be effective. Here, by genetic targeting of Survivin, an inhibitor of apoptosis protein (IAP) that plays dual roles in mitosis and cell survival, we identified a tumor necrosis factor alpha (TNF alpha)-mediated synergistic lethal effect between senescence and apoptosis sensitization in malignant HCCs. Survivin deficiency results in mitosis defect-associated senescence in HCC cells, which triggers local inflammation and increased TNF alpha. Survivin inactivation also sensitizes HCC cells to TNF alpha-triggered cell death, which leads to marked HCC regression. Based on these findings, we designed a combination treatment using mitosis inhibitor and proapoptosis compounds. This treatment recapitulates the therapeutic effect of Survivin deletion and effectively eliminates HCCs, thus representing a potential strategy for HCC therapy. Conclusion: Survivin ablation dramatically suppresses human and mouse HCCs by triggering senescence-associated TNF alpha and sensitizing HCC cells to TNF alpha-induced cell death. Combined use of mitotic inhibitor and second mitochondrial-derived activator of caspases mimetic can induce senescence-associated TNF alpha and enhance TNF alpha-induced cell death and synergistically eliminate HCC.