Hepatocellular carcinoma repression by TNFα-mediated synergistic lethal effect of mitosis defect-induced senescence and cell death sensitization

Dan Li, Jing Fu, Min Du, Haibin Zhang, Lu Li, Jin Cen, Weiyun Li, Xiaotao Chen, Yunfei Lin, Edward M. Conway, Eli Pikarsky, Hongyan Wang, Guoyu Pan, Yuan Ji*, Hong Yang Wang, Lijian Hui

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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 (TNFα)-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 TNFα. Survivin inactivation also sensitizes HCC cells to TNFα-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 TNFα and sensitizing HCC cells to TNFα-induced cell death. Combined use of mitotic inhibitor and second mitochondrial-derived activator of caspases mimetic can induce senescence-associated TNFα and enhance TNFα-induced cell death and synergistically eliminate HCC. (Hepatology 2016;64:1105-1120).

Original languageAmerican English
Pages (from-to)1105-1120
Number of pages16
JournalHepatology
Volume64
Issue number4
DOIs
StatePublished - 1 Oct 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 The Authors. (Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

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