Abstract
Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) can induce apoptosis in cancer cells while sparing normal cells, thereby leading to the development of TRAIL receptor agonists for cancer treatment. However, these agonist‐based therapeutics exhibit little clinical benefits due to the lack of biomarkers to predict whether patients are responsive to the treatment, as well as determine the resistance of cancer cells to TRAIL‐based agonists. Our previous study has demonstrated that ISG12a enhances TRAIL‐induced apoptosis and might serve as a biomarker to predict the TRAIL response. The downstream mechanism by which ISG12a augments TRAIL‐induced apoptosis remains to be elucidated. In this study, we found that ISG12a was localized in the mitochondria and nucleus and augmented TRAIL‐induced apoptosis through intrinsic apoptotic pathway. In addition, ISG12a interacted with NR4A1 and promoted its nuclear‐to‐cytoplasm translocation. Upon translocate to cytoplasm, NR4A1 targeted mitochondria and induced Bcl2 conformational change, thereby exposing its BH3 domain. Moreover, TRAIL treatment can induce NR4A1 expression through the activation of NF‐κB in TRAIL‐resistant Huh7 hepatoma cells. Knockdown of NR4A1 could overcome TRAIL resistance. However, in TRAIL‐sensitive LH86 liver cancer cells, TRAIL activated the Jun N‐terminal kinases signalling pathway. Overall, these results showed that both ISG12a and its interaction partner NR4A1 are involved in TRAIL‐mediated apoptosis in hepatoma cells.
Highlights
The tumour necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) is a member of the TNF superfamily and shares sequence ho‐ mology with Fas ligand and TNF.[1]
We previously reported that high expression level of ISG12a was positively associated with Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptosis in hepatocellular carcinoma (HCC) cells.[17]
TRAIL treatment activated higher Bax activity by promoting its 6A7 conformational change in ISG12a‐ overexpressing Huh[7] cells compared with vector expression cells (Figure 2F). These results suggested that ISG12a augments TRAIL‐induced apoptosis in hepatoma cells through mitochon‐ drial‐dependent apoptotic pathway
Summary
The tumour necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) is a member of the TNF superfamily and shares sequence ho‐ mology with Fas ligand and TNF.[1]. TRAIL activates a non‐apoptotic pathway, such as NF‐κB signalling pathway, thereby resulting in resistance to TRAIL‐induced apoptosis.[4]. IFN‐α induces apoptosis in myeloma cells and in solid tumours through induction of TRAIL.[6,7]. The FAM14 family member G1P3 is another ISG that antagonized TRAIL‐induced apoptosis through the inhibition of intrinsic apoptotic pathway.[10]. When localized to the inner nuclear membrane, ISG12a inter‐ acts with NR4A1 and inhibits its transcription activity.[15]. Whether the interaction between ISG12a and NR4A1 is involved in TRAIL‐induced apoptosis in hepatocellular carcinoma (HCC) is still unknown. We report that ISG12a is lo‐ calized to the mitochondria and nuclear membrane in HCC cells and promotes the translocation of NR4A1 from nucleus to cytoplasm. ISG12a augments TRAIL‐induced apoptosis by activating the intrin‐ sic apoptotic pathway. NR4A1 knockdown was able to overcome TRAIL resistance in hepatocellular carcinoma cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
