Hepatocellular carcinoma (HCC) is a dreaded disease worldwide lacking effective therapies.
Recently, new therapeutic strategy for this dreaded disease has been raised by Chinese researchers. In recent work by Prof. HUI Lijian’s lab at Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences(CAS) and co-workers, revealed that inhibitor of apoptosis protein, Survivin, played important roles in HCC development. This work was published in Hepatology.
In this work, they found that, Survivin ablation dramatically suppresses human and mouse HCCs by triggering senescence-associated Tumor Necrosis Factor α (TNFα) and sensitizing HCC cells to TNFα-induced cell death. Combined use of mitotic inhibitor and SMAC mimetic can induce senescence-associated TNFα and enhance TNFα-induced cell death and synergistically eliminate HCC.
In the early studies, Prof. HUI Lijian’s lab found that Survivin played important roles for the survival of HCC initiating cells (Min, et al, Nature Cell Biology, 2012) and inducible ablation of Survivin in adult liver does not affect liver homeostasis during a long life period (Li, et al, Hepatology, 2013). These data support the notion that Survivin is an ideal target for HCC therapy.
Survivin has been considered as a key oncogene in liver carcinogenesis. However, due to the small molecular size, it is so far unsuccessful in developing inhibitors against Survivin. A comprehensive understanding of molecular mechanisms controlled by Survivin may lead to developing novel anti-HCC strategy by targeting its downstream pathways.
The authors found a near-complete HCC regression upon genetic deletion of Survivin in HCCs. Importantly, thorough characterization of Survivin downstream mechanisms led to an unexpected finding of a TNFα-mediated synergistic lethal effect between senescence and apoptosis sensitization on eliminating both senescent and non-senescent HCC cells. Survivin deficiency induces mitosis defect-caused senescence and increases TNFα in HCCs. Moreover, Survivin deletion hypersensitizes both senescent and neighboring non-senescent HCC cells to TNFα-triggered cell death.
By taking advantage of these findings, the authors additionally designed and validated a new HCC therapeutic strategy by combination use of mitotic inhibitor and SMAC mimetic to induce mitosis arrest-associated senescence and to enhance TNFα-induced cell death, respectively.
The study entitled “Hepatocellular carcinoma repression by TNFα-mediated synergistic lethal effect of mitosis defect-induced senescence and cell death sensitization” has been published in Hepatology on 2016 May 14.
This work was supported by grants from the Ministry of Science and Technology (MOST) of China, National Natural Science Foundation of China project (NSFC), Shanghai Science and Technology Committee.
AUTHOR CONTACT:
HUI Lijian
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, Shanghai, China
Phone:86-21-54921329;
E-mail: huilab@sibcb.ac.cn
KEYWORDS:
Hepatocellular carcinoma, HCC, Survivin, Hepatocellular carcinoma repression, senescence-associated TNFα, TNFα-induced cell death
NEWS ABSTRACT:
Recently, new therapeutic strategy for the dreaded disease Hepatocellular carcinoma has been raised by Chinese researchers. In recent work by Prof. HUI Lijian’s lab at Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences(CAS) and co-workers, revealed that inhibitor of apoptosis protein, Survivin, played important roles in HCC development. Survivin ablation dramatically suppresses human and mouse HCCs by triggering senescence-associated Tumor Necrosis Factor α (TNFα) and sensitizing HCC cells to TNFα-induced cell death. Combined use of mitotic inhibitor and SMAC mimetic can induce senescence-associated TNFα and enhance TNFα-induced cell death and synergistically eliminate HCC. This work was published in Hepatology.
Figure: The schematic of TNFα-mediated synergistic lethal effect of senescence and apoptosis sensitization, Survivin depletion induce impaired mitosis and senescence in cancer cells, infiltration of inflammatory cells and senescence-associated TNFα trigger cell death in senescent and neighboring non-senescent cancer cells lacking Survivin. (Image provided by Prof. HUI Lijian’s lab)
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