Regulation of pancreatic cancer TRAIL resistance by protein O-GlcNAcylation
| Autor: | Shan-zhong Yang, Tong Zhou, Jay M. McDonald, Yabing Chen, Xinyang Zhao, Yong Sun, Kaiyu Yuan, Fei Xu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Mice Nude TRAIL Apoptosis N-Acetylglucosaminyltransferases Article Pathology and Forensic Medicine Acetylglucosamine TNF-Related Apoptosis-Inducing Ligand 03 medical and health sciences Pancreatic Cancer Mice 0302 clinical medicine O-GlcNAcylation In vivo Pancreatic cancer Cell Line Tumor medicine Animals Humans FADD DR5 Molecular Biology chemistry.chemical_classification Mice Knockout Gene knockdown biology Signal transducing adaptor protein Cell Biology medicine.disease Pancreatic Neoplasms 030104 developmental biology Enzyme chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Signal Transduction |
| Zdroj: | Laboratory investigation; a journal of technical methods and pathology |
| ISSN: | 1530-0307 0023-6837 |
| Popis: | TRAIL-activating therapy is promising in treating various cancers, including pancreatic cancer, a highly malignant neoplasm with poor prognosis. However, many pancreatic cancer cells are resistant to TRAIL-induced apoptosis despite their expression of intact death receptors (DRs). Protein O-GlcNAcylation is a versatile posttranslational modification that regulates various biological processes. Elevated protein O-GlcNAcylation has been recently linked to cancer cell growth and survival. In this study, we evaluated the role of protein O-GlcNAcylation in pancreatic cancer TRAIL resistance, and identified higher levels of O-GlcNAcylation in TRAIL-resistant pancreatic cancer cells. With gain- and loss-of-function of the O-GlcNAc-adding enzyme, O-GlcNActransferase (OGT), we determined that increasing O-GlcNAcylation rendered TRAIL-sensitive cells more resistant to TRA-8-induced apoptosis, while inhibiting O-GlcNAcylation promoted TRA-8-induced apoptosis in TRAIL-resistance cells. Furthermore, we demonstrated that OGT knockdown sensitized TRAIL-resistant cells to TRA-8 therapy in a mouse model in vivo. Mechanistic studies revealed direct O-GlcNAc modifications of DR5, which regulated TRA-8-induced DR5 oligomerization. We further defined that DR5 O-GlcNAcylation was independent of FADD, the adapter protein for the downstream death-inducing signaling. These studies have demonstrated an important role of protein O-GlcNAcylation in regulating TRAIL resistance of pancreatic cancer cells; and uncovered the contribution of O-GlcNAcylation to DR5 oligomerization and thus mediating DR-inducing signaling. The authors have demonstrated an important new role of protein O-GlcNAcylation in regulating pancreatic cancer TRAIL resistance; and uncovered the contribution of O-GlcNAcylation to TRAIL activation-induced oligomerization of death receptor 5 and apoptosis signaling. These findings support the potential use of O-GlcNAcylation inhibitors to enhance efficacy of TRAIL therapy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink