p62 aggregates mediated Caspase 8 activation is responsible for progression of ovarian cancer
Autor: | Jing Su, Xin-Ru Zhong, Li-Chao Zhang, Sihang Yu, Xiao-Yu Yan, Yong Zhang, Liankun Sun, Yanan Liu |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
autophagy Cell Survival Caspase 8 03 medical and health sciences 0302 clinical medicine Ubiquitin In vivo Cell Line Tumor Sequestosome-1 Protein Biomarkers Tumor medicine Humans Aged Ovarian Neoplasms Cisplatin biology Chemistry p62 Autophagy apoptosis RNA-Binding Proteins Cancer Original Articles Cell Biology medicine.disease ovarian cancer 030104 developmental biology Apoptosis 030220 oncology & carcinogenesis Disease Progression Cancer research biology.protein Molecular Medicine Female Original Article Ovarian cancer Signal Transduction medicine.drug |
Zdroj: | Journal of Cellular and Molecular Medicine |
ISSN: | 1582-4934 1582-1838 |
Popis: | Increasing evidence suggests that p62/SQSTM1 functions as a signalling centre in cancer. However, the role of p62 in tumour development depends on the interacting factors it recruits and its precise regulatory mechanism remains unclear. In this study, we investigated the pro‐death signalling recruitment of p62 with the goal of improving anti‐tumour drug effects in ovarian cancer treatment. We found that p62 with Caspase 8 high expression is correlated with longer survival time compared with cases of low Caspase 8 expression in ovarian cancer. In vivo experiments suggested that insoluble p62 and ubiquitinated protein accumulation induced by autophagy impairment promoted the activation of Caspase 8 and increased cell sensitivity to cisplatin. Furthermore, p62 functional domain UBA and LIR mutants regulated autophagic flux and attenuated Caspase 8 activation, which indicates that autophagic degradation is involved in p62‐mediated activation of Caspase 8 in ovarian cancer cells. Collectively, our study demonstrates that p62 promotes Caspase 8 activation through autophagy flux blockage with cisplatin treatment. We have provided evidence that autophagy induction followed by its blockade increases cell sensitivity to chemotherapy which is dependent on p62‐Caspase 8 mediated apoptosis signalling. p62 exhibits pro‐death functions through its interaction with Caspase 8. p62 and Caspase 8 may become novel prognostic biomarkers and oncotargets for ovarian cancer treatment. |
Databáze: | OpenAIRE |
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