Article ; Online: GSK-3β controls autophagy by modulating LKB1-AMPK pathway in prostate cancer cells.
2016 Volume 76, Issue 2, Page(s) 172–183
Abstract: ... in GSK-3β inhibition-triggered autophagy.: Methods: Prostate cancer PC-3 and DU145 cells were used ... in controlling autophagy induction by modulating the activation of LKB1-AMPK pathway after serum deprivation. ... activated protein kinase (AMPK) activation in prostate cancer PC-3 cells. In parallel with increased LC-3B ...
| Abstract | Background: Glycogen synthase kinase 3β (GSK3B, GSK-3β) is a multi-functional protein kinase involved in various cellular processes and its activity elevates after serum deprivation. We have shown that inhibition of GSK-3β activity triggered a profound autophagic response and subsequent necrotic cell death after serum deprivation in prostate cancer cells. In this study, we dissected the mechanisms involved in GSK-3β inhibition-triggered autophagy. Methods: Prostate cancer PC-3 and DU145 cells were used in the study. Multiple GSK-3β specific inhibitors were used including small chemicals TDZD8, Tideglusib, TWS119, and peptide L803-mts. Western blot assay coupled with phospho-specific antibodies were used in detecting signal pathway activation. ATP levels were assessed with ATPLite kit and HPLC methods. Autophagy response was determined by evaluating Microtubule-associated proteins 1A/1B light chain 3B (LC3B) processing and p62 protein stability in Western blot assays. Immunofluorescent microscopy was used to detect LKB1 translocation. Results: Inhibition of GSK-3β activity resulted in a significant decline of cellular ATP production, leading to a significant increase of AMP/ATP ratio, a strong trigger of AMP-activated protein kinase (AMPK) activation in prostate cancer PC-3 cells. In parallel with increased LC-3B biosynthesis and p62 protein reduction, the classical sign of autophagy induction, AMPK was activated after inhibition of GSK-3β activity. Further analysis revealed that Liver kinase B1 (LKB1) but not Calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ) is involved in AMPK activation and autophagy induction triggered by GSK-3β inhibition. Meanwhile, GSK-3β inhibition promoted LKB1 translocation from nuclear to cytoplasmic compartment and enhanced LKB1 interaction with its regulatory partners Mouse protein-25 (MO25) and STE20-related adaptor (STRAD). Conclusions: In conclusion, our data suggest that GSK-3β plays an important role in controlling autophagy induction by modulating the activation of LKB1-AMPK pathway after serum deprivation. |
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| MeSH term(s) | AMP-Activated Protein Kinases/physiology ; Animals ; Autophagy/drug effects ; Autophagy/physiology ; Cell Line, Tumor ; Enzyme Inhibitors/pharmacology ; Glycogen Synthase Kinase 3/antagonists & inhibitors ; Glycogen Synthase Kinase 3/physiology ; Glycogen Synthase Kinase 3 beta ; Humans ; Male ; Mice ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Protein-Serine-Threonine Kinases/physiology ; Signal Transduction/drug effects ; Signal Transduction/physiology | |||||
| Chemical Substances | Enzyme Inhibitors ; STK11 protein, human (EC 2.7.1.-) ; GSK3B protein, human (EC 2.7.11.1) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Gsk3b protein, mouse (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; AMP-Activated Protein Kinases (EC 2.7.11.31) | |||||
| Language | English | |||||
| Publishing date | 2016-02 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 604707-5 | |||||
| ISSN | 1097-0045 ; 0270-4137 | |||||
| ISSN (online) | 1097-0045 | |||||
| ISSN | 0270-4137 | |||||
| DOI | 10.1002/pros.23106 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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